<?xml version="1.0" encoding="us-ascii"?>
<!-- DFIN ActiveDisclosure(SM) XBRL Linkbase Document - http://www.dfinsolutions.com/ -->
<!-- Creation Date      : 2021-03-11T17:26:25.4467664+00:00 -->
<!-- Version            : 5.0.1.571 -->
<!-- Package ID         : 5dfae4c47c2a4366a6c04c7749cf7ec4 -->
<!-- Copyright (c) 2021 Donnelley Financial Solutions, Inc. All Rights Reserved. -->
<link:linkbase xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <link:arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all" arcroleURI="http://xbrl.org/int/dim/arcrole/all" />
  <link:arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default" arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default" />
  <link:arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain" arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain" />
  <link:arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member" arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member" />
  <link:arcroleRef xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension" arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension" />
  <link:roleRef xlink:type="simple" xlink:href="sndx-20201231.xsd#TemplateLink" roleURI="http://www.syndax.com/20201231/role/TemplateLink" />
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/StatementConsolidatedStatementsOfStockholdersEquity" xlink:href="sndx-20201231.xsd#Role_StatementConsolidatedStatementsOfStockholdersEquity" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/StatementConsolidatedStatementsOfStockholdersEquity">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetIncomeLoss" xlink:type="locator" xlink:label="us-gaap_NetIncomeLoss" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued" xlink:type="locator" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockRepurchasedAndRetiredDuringPeriodShares" xlink:type="locator" xlink:label="us-gaap_StockRepurchasedAndRetiredDuringPeriodShares" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockRepurchasedAndRetiredDuringPeriodValue" xlink:type="locator" xlink:label="us-gaap_StockRepurchasedAndRetiredDuringPeriodValue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AccountingStandardsUpdateExtensibleList" xlink:type="locator" xlink:label="us-gaap_AccountingStandardsUpdateExtensibleList" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AdjustmentToAdditionalPaidInCapitalIncomeTaxEffectFromShareBasedCompensationNet" xlink:type="locator" xlink:label="us-gaap_AdjustmentToAdditionalPaidInCapitalIncomeTaxEffectFromShareBasedCompensationNet" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodSharesExerciseOfWarrants" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodSharesExerciseOfWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueWarrantsExercised" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueWarrantsExercised" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax" xlink:type="locator" xlink:label="us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" xlink:type="locator" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodValueEmployeeStockPurchasePlan" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueEmployeeStockPurchasePlan" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AdjustmentsToAdditionalPaidInCapitalRepricingWarrant" xlink:type="locator" xlink:label="sndx_AdjustmentsToAdditionalPaidInCapitalRepricingWarrant" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AdjustmentsToAdditionalPaidInCapitalDeemedDividendFromRepricingWarrants" xlink:type="locator" xlink:label="sndx_AdjustmentsToAdditionalPaidInCapitalDeemedDividendFromRepricingWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueCommonStockWarrantWithDirectOffering" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueCommonStockWarrantWithDirectOffering" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodSharesPreFundedCommonStockWarrantsFromDirectOffering" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodSharesPreFundedCommonStockWarrantsFromDirectOffering" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrantsFromDirectOffering" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrantsFromDirectOffering" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodSharesDirectOffering" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodSharesDirectOffering" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueDirectOffering" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueDirectOffering" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodSharesWarrantExerciseCashless" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodSharesWarrantExerciseCashless" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueWarrantExerciseCashless" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueWarrantExerciseCashless" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodValueStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodValueStockOptionsExercised" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodSharesAtTheMarketOfferingNet" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodSharesAtTheMarketOfferingNet" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueAtTheMarketOfferingNet" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueAtTheMarketOfferingNet" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SharesOutstanding" xlink:type="locator" xlink:label="us-gaap_SharesOutstanding" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockholdersEquity" xlink:type="locator" xlink:label="us-gaap_StockholdersEquity" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FollowOnPublicOfferingTwoMember" xlink:type="locator" xlink:label="sndx_FollowOnPublicOfferingTwoMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FollowOnPublicOfferingOneMember" xlink:type="locator" xlink:label="sndx_FollowOnPublicOfferingOneMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_DirectPlacementOfferingMember" xlink:type="locator" xlink:label="sndx_DirectPlacementOfferingMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:type="locator" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CumulativeEffectPeriodOfAdoptionAdjustmentMember" xlink:type="locator" xlink:label="srt_CumulativeEffectPeriodOfAdoptionAdjustmentMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CumulativeEffectPeriodOfAdoptionDomain" xlink:type="locator" xlink:label="srt_CumulativeEffectPeriodOfAdoptionDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CumulativeEffectPeriodOfAdoptionDomain" xlink:type="locator" xlink:label="srt_CumulativeEffectPeriodOfAdoptionDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CumulativeEffectPeriodOfAdoptionAxis" xlink:type="locator" xlink:label="srt_CumulativeEffectPeriodOfAdoptionAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RetainedEarningsMember" xlink:type="locator" xlink:label="us-gaap_RetainedEarningsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeMember" xlink:type="locator" xlink:label="us-gaap_AccumulatedOtherComprehensiveIncomeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AdditionalPaidInCapitalMember" xlink:type="locator" xlink:label="us-gaap_AdditionalPaidInCapitalMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockMember" xlink:type="locator" xlink:label="us-gaap_CommonStockMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementEquityComponentsAxis" xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementTable" xlink:type="locator" xlink:label="us-gaap_StatementTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementLineItems" xlink:type="locator" xlink:label="us-gaap_StatementLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AdditionalPaidInCapitalMember" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AccumulatedOtherComprehensiveIncomeMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_RetainedEarningsMember" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="srt_CumulativeEffectPeriodOfAdoptionAxis" order="10180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_CumulativeEffectPeriodOfAdoptionAxis" xlink:to="srt_CumulativeEffectPeriodOfAdoptionDomain_2" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_CumulativeEffectPeriodOfAdoptionAxis" xlink:to="srt_CumulativeEffectPeriodOfAdoptionDomain" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_CumulativeEffectPeriodOfAdoptionDomain" xlink:to="srt_CumulativeEffectPeriodOfAdoptionAdjustmentMember" order="10230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" order="10240.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain_2" order="10250.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" order="10270.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_DirectPlacementOfferingMember" order="10290.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_FollowOnPublicOfferingOneMember" order="10310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_FollowOnPublicOfferingTwoMember" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockholdersEquity" order="10360.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_SharesOutstanding" order="10380.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueAtTheMarketOfferingNet" order="10500.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodSharesAtTheMarketOfferingNet" order="10520.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueStockOptionsExercised" order="10640.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" order="10660.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueWarrantExerciseCashless" order="10780.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodSharesWarrantExerciseCashless" order="10800.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueDirectOffering" order="10920.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodSharesDirectOffering" order="10940.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrantsFromDirectOffering" order="11060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodSharesPreFundedCommonStockWarrantsFromDirectOffering" order="11080.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueCommonStockWarrantWithDirectOffering" order="11200.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_AdjustmentsToAdditionalPaidInCapitalDeemedDividendFromRepricingWarrants" order="11340.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_AdjustmentsToAdditionalPaidInCapitalRepricingWarrant" order="11480.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueEmployeeStockPurchasePlan" order="11620.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" order="11640.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" order="11760.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_OtherComprehensiveIncomeUnrealizedHoldingGainLossOnSecuritiesArisingDuringPeriodNetOfTax" order="11900.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueWarrantsExercised" order="12040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodSharesExerciseOfWarrants" order="12060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentToAdditionalPaidInCapitalIncomeTaxEffectFromShareBasedCompensationNet" order="12180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AccountingStandardsUpdateExtensibleList" order="12460.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockRepurchasedAndRetiredDuringPeriodValue" order="12600.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockRepurchasedAndRetiredDuringPeriodShares" order="12620.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued" order="12740.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetIncomeLoss" order="12880.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/StatementConsolidatedStatementsOfStockholdersEquityParenthetical" xlink:href="sndx-20201231.xsd#Role_StatementConsolidatedStatementsOfStockholdersEquityParenthetical" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/StatementConsolidatedStatementsOfStockholdersEquityParenthetical">
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrantOfferingExpenses" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrantOfferingExpenses" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrant" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrant" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueOfferingExpenses" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueOfferingExpenses" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueDirectOfferingCommonStockWarrant" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueDirectOfferingCommonStockWarrant" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodValueAtTheMarketOfferingExpenses" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodValueAtTheMarketOfferingExpenses" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockParOrStatedValuePerShare" xlink:type="locator" xlink:label="us-gaap_CommonStockParOrStatedValuePerShare" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FollowOnPublicOfferingTwoMember" xlink:type="locator" xlink:label="sndx_FollowOnPublicOfferingTwoMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FollowOnPublicOfferingOneMember" xlink:type="locator" xlink:label="sndx_FollowOnPublicOfferingOneMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_DirectPlacementOfferingMember" xlink:type="locator" xlink:label="sndx_DirectPlacementOfferingMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:type="locator" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementTable" xlink:type="locator" xlink:label="us-gaap_StatementTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementLineItems" xlink:type="locator" xlink:label="us-gaap_StatementLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_DirectPlacementOfferingMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_FollowOnPublicOfferingOneMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_FollowOnPublicOfferingTwoMember" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CommonStockParOrStatedValuePerShare" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueAtTheMarketOfferingExpenses" order="10280.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueDirectOfferingCommonStockWarrant" order="10400.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValueOfferingExpenses" order="10520.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrant" order="10640.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="sndx_StockIssuedDuringPeriodValuePreFundedCommonStockWarrantOfferingExpenses" order="10760.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/StatementConsolidatedStatementsOfCashFlows" xlink:href="sndx-20201231.xsd#Role_StatementConsolidatedStatementsOfCashFlows" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/StatementConsolidatedStatementsOfCashFlows">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RestrictedCash" xlink:type="locator" xlink:label="us-gaap_RestrictedCash" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations" xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromPaymentsForOtherFinancingActivities" xlink:type="locator" xlink:label="us-gaap_ProceedsFromPaymentsForOtherFinancingActivities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_ProceedsFromStockOptionsExercised" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromStockPlans" xlink:type="locator" xlink:label="us-gaap_ProceedsFromStockPlans" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromDebtNetOfIssuanceCosts" xlink:type="locator" xlink:label="us-gaap_ProceedsFromDebtNetOfIssuanceCosts" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromIssuanceOfCommonStock" xlink:type="locator" xlink:label="us-gaap_ProceedsFromIssuanceOfCommonStock" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities" xlink:type="locator" xlink:label="us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PaymentsToAcquireShortTermInvestments" xlink:type="locator" xlink:label="us-gaap_PaymentsToAcquireShortTermInvestments" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:type="locator" xlink:label="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncreaseDecreaseInContractWithCustomerLiability" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInContractWithCustomerLiability" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncreaseDecreaseInAccountsPayable" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccountsPayable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OtherNoncashIncomeExpense" xlink:type="locator" xlink:label="us-gaap_OtherNoncashIncomeExpense" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensation" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensation" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PaidInKindInterest" xlink:type="locator" xlink:label="us-gaap_PaidInKindInterest" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NoncashOperatingLeaseExpense" xlink:type="locator" xlink:label="sndx_NoncashOperatingLeaseExpense" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" xlink:type="locator" xlink:label="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_DepreciationAndRelatedAdjustment" xlink:type="locator" xlink:label="sndx_DepreciationAndRelatedAdjustment" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:type="locator" xlink:label="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProfitLoss" xlink:type="locator" xlink:label="us-gaap_ProfitLoss" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PrivatePlacementMember" xlink:type="locator" xlink:label="us-gaap_PrivatePlacementMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AtTheMarketStockOfferingMember" xlink:type="locator" xlink:label="sndx_AtTheMarketStockOfferingMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FollowOnPublicOfferingsMember" xlink:type="locator" xlink:label="sndx_FollowOnPublicOfferingsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:type="locator" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementTable" xlink:type="locator" xlink:label="us-gaap_StatementTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementLineItems" xlink:type="locator" xlink:label="us-gaap_StatementLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" order="10250.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" order="10280.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" order="10310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_FollowOnPublicOfferingsMember" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sndx_AtTheMarketStockOfferingMember" order="10350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="us-gaap_PrivatePlacementMember" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" order="10400.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_ProfitLoss" order="10520.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" order="10580.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="sndx_DepreciationAndRelatedAdjustment" order="10700.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" order="10760.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="sndx_NoncashOperatingLeaseExpense" order="10820.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_PaidInKindInterest" order="10880.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_ShareBasedCompensation" order="10940.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_OtherNoncashIncomeExpense" order="11000.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" order="11060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" order="11180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInAccountsPayable" order="11240.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInContractWithCustomerLiability" order="11300.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" order="11360.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities" order="11420.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" order="11480.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" order="11600.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_PaymentsToAcquireShortTermInvestments" order="11660.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromSaleAndMaturityOfAvailableForSaleSecurities" order="11720.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivities" order="11780.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" order="11840.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromIssuanceOfCommonStock" order="11960.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromDebtNetOfIssuanceCosts" order="12140.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromStockPlans" order="12200.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromStockOptionsExercised" order="12260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromPaymentsForOtherFinancingActivities" order="12320.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities" order="12380.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" order="12440.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations" order="12500.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CashAndCashEquivalentsAtCarryingValue" order="12650.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_RestrictedCash" order="12710.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureSummaryOfSignificantAccountingPoliciesAdditionalInformationDetail">
    <link:loc xlink:href="sndx-20201231.xsd#sndx_IndemnificationObligationsClaimsReserves" xlink:type="locator" xlink:label="sndx_IndemnificationObligationsClaimsReserves" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LossContingencyPendingClaimsNumber" xlink:type="locator" xlink:label="us-gaap_LossContingencyPendingClaimsNumber" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PercentageOfIncomeTaxContingencyRealized" xlink:type="locator" xlink:label="sndx_PercentageOfIncomeTaxContingencyRealized" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_IncreaseDecreaseInResearchAndDevelopmentExpense" xlink:type="locator" xlink:label="sndx_IncreaseDecreaseInResearchAndDevelopmentExpense" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_CostsRelatedToCostSharingCollaborations" xlink:type="locator" xlink:label="sndx_CostsRelatedToCostSharingCollaborations" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_TangibleAssetImpairmentCharges" xlink:type="locator" xlink:label="us-gaap_TangibleAssetImpairmentCharges" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentUsefulLife" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentUsefulLife" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NumberOfOperatingSegments" xlink:type="locator" xlink:label="us-gaap_NumberOfOperatingSegments" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IndemnificationGuaranteeMember" xlink:type="locator" xlink:label="us-gaap_IndemnificationGuaranteeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_GuaranteeObligationsNatureDomain" xlink:type="locator" xlink:label="us-gaap_GuaranteeObligationsNatureDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_GuaranteeObligationsNatureDomain" xlink:type="locator" xlink:label="us-gaap_GuaranteeObligationsNatureDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_GuaranteeObligationsByNatureAxis" xlink:type="locator" xlink:label="us-gaap_GuaranteeObligationsByNatureAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CollaborativeArrangementMember" xlink:type="locator" xlink:label="us-gaap_CollaborativeArrangementMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:type="locator" xlink:label="us-gaap_ArrangementsAndNonarrangementTransactionsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:type="locator" xlink:label="us-gaap_ArrangementsAndNonarrangementTransactionsMember_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_TypeOfArrangementAxis" xlink:type="locator" xlink:label="us-gaap_TypeOfArrangementAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SummaryOfSignificantAccountingPoliciesTable" xlink:type="locator" xlink:label="sndx_SummaryOfSignificantAccountingPoliciesTable" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:type="locator" xlink:label="sndx_SummaryOfSignificantAccountingPoliciesLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="sndx_SummaryOfSignificantAccountingPoliciesTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesTable" xlink:to="srt_RangeAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesTable" xlink:to="us-gaap_TypeOfArrangementAxis" order="10120.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_TypeOfArrangementAxis" xlink:to="us-gaap_ArrangementsAndNonarrangementTransactionsMember_2" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_TypeOfArrangementAxis" xlink:to="us-gaap_ArrangementsAndNonarrangementTransactionsMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:to="us-gaap_CollaborativeArrangementMember" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesTable" xlink:to="us-gaap_GuaranteeObligationsByNatureAxis" order="10320.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_GuaranteeObligationsByNatureAxis" xlink:to="us-gaap_GuaranteeObligationsNatureDomain_2" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_GuaranteeObligationsByNatureAxis" xlink:to="us-gaap_GuaranteeObligationsNatureDomain" order="10350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_GuaranteeObligationsNatureDomain" xlink:to="us-gaap_IndemnificationGuaranteeMember" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="us-gaap_NumberOfOperatingSegments" order="10420.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentUsefulLife" order="10470.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="us-gaap_TangibleAssetImpairmentCharges" order="10560.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="sndx_CostsRelatedToCostSharingCollaborations" order="10610.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="sndx_IncreaseDecreaseInResearchAndDevelopmentExpense" order="10650.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="sndx_PercentageOfIncomeTaxContingencyRealized" order="10800.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="us-gaap_LossContingencyPendingClaimsNumber" order="10850.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_SummaryOfSignificantAccountingPoliciesLineItems" xlink:to="sndx_IndemnificationObligationsClaimsReserves" order="10870.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureRevenueFromContractWithCustomersAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureRevenueFromContractWithCustomersAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureRevenueFromContractWithCustomersAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ContractWithCustomerLiability" xlink:type="locator" xlink:label="us-gaap_ContractWithCustomerLiability" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RevenueRemainingPerformanceObligationExpectedTimingOfSatisfactionYear1" xlink:type="locator" xlink:label="us-gaap_RevenueRemainingPerformanceObligationExpectedTimingOfSatisfactionYear1" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RevenueRemainingPerformanceObligation" xlink:type="locator" xlink:label="us-gaap_RevenueRemainingPerformanceObligation" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ContractWithCustomerLiabilityRevenueRecognized" xlink:type="locator" xlink:label="us-gaap_ContractWithCustomerLiabilityRevenueRecognized" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_RevenueFromContractWithCustomerMilestoneMethodFactors" xlink:type="locator" xlink:label="sndx_RevenueFromContractWithCustomerMilestoneMethodFactors" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UpfrontPaymentAllocatedToLicenseFee" xlink:type="locator" xlink:label="sndx_UpfrontPaymentAllocatedToLicenseFee" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UpfrontPaymentAllocatedToEquityPurchaseFairValue" xlink:type="locator" xlink:label="sndx_UpfrontPaymentAllocatedToEquityPurchaseFairValue" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PeriodOfTerminationAfterFirstCommercialSaleOfFirstLicensedProduct" xlink:type="locator" xlink:label="sndx_PeriodOfTerminationAfterFirstCommercialSaleOfFirstLicensedProduct" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PotentialMilestonePaymentsReceivable" xlink:type="locator" xlink:label="sndx_PotentialMilestonePaymentsReceivable" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NonRefundableUpFrontPaymentReceived" xlink:type="locator" xlink:label="sndx_NonRefundableUpFrontPaymentReceived" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UpfrontPaymentAllocatedToEquityPurchase" xlink:type="locator" xlink:label="sndx_UpfrontPaymentAllocatedToEquityPurchase" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UpfrontPaymentsReceived" xlink:type="locator" xlink:label="sndx_UpfrontPaymentsReceived" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_KyowaKirinCoLtdMember" xlink:type="locator" xlink:label="sndx_KyowaKirinCoLtdMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CounterpartyNameAxis" xlink:type="locator" xlink:label="srt_CounterpartyNameAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LicenseAgreementMember" xlink:type="locator" xlink:label="sndx_LicenseAgreementMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:type="locator" xlink:label="us-gaap_ArrangementsAndNonarrangementTransactionsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_TypeOfArrangementAxis" xlink:type="locator" xlink:label="us-gaap_TypeOfArrangementAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleTable" xlink:type="locator" xlink:label="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:type="locator" xlink:label="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleTable" xlink:to="us-gaap_TypeOfArrangementAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_TypeOfArrangementAxis" xlink:to="us-gaap_ArrangementsAndNonarrangementTransactionsMember" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:to="sndx_LicenseAgreementMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleTable" xlink:to="srt_CounterpartyNameAxis" order="10180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain_2" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_KyowaKirinCoLtdMember" order="10230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleTable" xlink:to="srt_RangeAxis" order="10320.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10390.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_UpfrontPaymentsReceived" order="10980.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_UpfrontPaymentAllocatedToEquityPurchase" order="11000.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_NonRefundableUpFrontPaymentReceived" order="11020.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_PotentialMilestonePaymentsReceivable" order="11040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_PeriodOfTerminationAfterFirstCommercialSaleOfFirstLicensedProduct" order="11060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_UpfrontPaymentAllocatedToEquityPurchaseFairValue" order="11110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_UpfrontPaymentAllocatedToLicenseFee" order="11130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="sndx_RevenueFromContractWithCustomerMilestoneMethodFactors" order="11180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="us-gaap_ContractWithCustomerLiabilityRevenueRecognized" order="11220.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="us-gaap_RevenueRemainingPerformanceObligation" order="11290.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="us-gaap_RevenueRemainingPerformanceObligationExpectedTimingOfSatisfactionYear1" order="11310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NewAccountingPronouncementsOrChangeInAccountingPrincipleLineItems" xlink:to="us-gaap_ContractWithCustomerLiability" order="11380.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureLeasesAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureLeasesAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureLeasesAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FinanceLeaseLiabilityPaymentsDue" xlink:type="locator" xlink:label="us-gaap_FinanceLeaseLiabilityPaymentsDue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LesseeOperatingLeaseOptionToExtend" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseOptionToExtend" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OperatingLeasePayments" xlink:type="locator" xlink:label="us-gaap_OperatingLeasePayments" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OperatingLeaseExpense" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseExpense" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OperatingLeaseLiability" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLiability" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OperatingLeaseRightOfUseAsset" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseRightOfUseAsset" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LeaseCommencementDate" xlink:type="locator" xlink:label="sndx_LeaseCommencementDate" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AreaOfRealEstateProperty" xlink:type="locator" xlink:label="us-gaap_AreaOfRealEstateProperty" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LessorOperatingLeaseTermOfContract" xlink:type="locator" xlink:label="us-gaap_LessorOperatingLeaseTermOfContract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LesseeOperatingLeaseExistenceOfOptionToTerminate" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseExistenceOfOptionToTerminate" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LesseeOperatingLeaseExistenceOfOptionToExtend" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseExistenceOfOptionToExtend" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventMember" xlink:type="locator" xlink:label="us-gaap_SubsequentEventMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventTypeDomain" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventTypeDomain" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventTypeAxis" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <link:loc xlink:href="https://xbrl.sec.gov/stpr/2018/stpr-2018-01-31.xsd#stpr_NY" xlink:type="locator" xlink:label="stpr_NY" />
    <link:loc xlink:href="https://xbrl.sec.gov/stpr/2018/stpr-2018-01-31.xsd#stpr_MA" xlink:type="locator" xlink:label="stpr_MA" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_SegmentGeographicalDomain" xlink:type="locator" xlink:label="srt_SegmentGeographicalDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_SegmentGeographicalDomain" xlink:type="locator" xlink:label="srt_SegmentGeographicalDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_StatementGeographicalAxis" xlink:type="locator" xlink:label="srt_StatementGeographicalAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LesseeLeaseDescriptionTable" xlink:type="locator" xlink:label="us-gaap_LesseeLeaseDescriptionTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LesseeLeaseDescriptionLineItems" xlink:type="locator" xlink:label="us-gaap_LesseeLeaseDescriptionLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_LesseeLeaseDescriptionTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_LesseeLeaseDescriptionTable" xlink:to="srt_StatementGeographicalAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_StatementGeographicalAxis" xlink:to="srt_SegmentGeographicalDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_StatementGeographicalAxis" xlink:to="srt_SegmentGeographicalDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_SegmentGeographicalDomain" xlink:to="stpr_MA" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_SegmentGeographicalDomain" xlink:to="stpr_NY" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_LesseeLeaseDescriptionTable" xlink:to="us-gaap_SubsequentEventTypeAxis" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain_2" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_LesseeOperatingLeaseExistenceOfOptionToExtend" order="10260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_LesseeOperatingLeaseExistenceOfOptionToTerminate" order="10280.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_LessorOperatingLeaseTermOfContract" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_AreaOfRealEstateProperty" order="10430.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="sndx_LeaseCommencementDate" order="10530.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_OperatingLeaseWeightedAverageRemainingLeaseTerm1" order="10630.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_OperatingLeaseRightOfUseAsset" order="10730.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_OperatingLeaseLiability" order="10830.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_OperatingLeaseWeightedAverageDiscountRatePercent" order="10930.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_OperatingLeaseExpense" order="11030.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_OperatingLeasePayments" order="11130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_LesseeOperatingLeaseOptionToExtend" order="11280.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_FinanceLeaseLiabilityPaymentsDue" order="11350.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureNetLossPerShareAttributableToCommonStockholdersComputationOfBasicAndDilutedNetLossPerShareAttributableToCommonStockholdersDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureNetLossPerShareAttributableToCommonStockholdersComputationOfBasicAndDilutedNetLossPerShareAttributableToCommonStockholdersDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureNetLossPerShareAttributableToCommonStockholdersComputationOfBasicAndDilutedNetLossPerShareAttributableToCommonStockholdersDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_WeightedAverageNumberOfShareOutstandingBasicAndDiluted" xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfShareOutstandingBasicAndDiluted" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingAbstract" xlink:type="locator" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EarningsPerShareBasicAndDiluted" xlink:type="locator" xlink:label="us-gaap_EarningsPerShareBasicAndDiluted" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" xlink:type="locator" xlink:label="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_Dividends" xlink:type="locator" xlink:label="us-gaap_Dividends" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetIncomeLoss" xlink:type="locator" xlink:label="us-gaap_NetIncomeLoss" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_NetIncomeLossAbstract" xlink:type="locator" xlink:label="us-gaap_NetIncomeLossAbstract" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_WarrantMember" xlink:type="locator" xlink:label="us-gaap_WarrantMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesNameDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EarningsPerShareBasicLineItems" xlink:type="locator" xlink:label="us-gaap_EarningsPerShareBasicLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" order="10020.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="us-gaap_AntidilutiveSecuritiesNameDomain_2" order="10060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="us-gaap_AntidilutiveSecuritiesNameDomain" order="10080.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_WarrantMember" order="10100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_NetIncomeLossAbstract" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetIncomeLossAbstract" xlink:to="us-gaap_NetIncomeLoss" order="10250.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetIncomeLossAbstract" xlink:to="us-gaap_Dividends" order="10310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_NetIncomeLossAbstract" xlink:to="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_EarningsPerShareBasicAndDiluted" order="10430.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingAbstract" order="10490.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_WeightedAverageNumberOfSharesOutstandingAbstract" xlink:to="us-gaap_WeightedAverageNumberOfShareOutstandingBasicAndDiluted" order="10610.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureNetLossPerShareAttributableToCommonStockholdersPotentialDilutiveSecuritiesExcludedFromComputationOfDilutedNetLossPerCommonShareDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureNetLossPerShareAttributableToCommonStockholdersPotentialDilutiveSecuritiesExcludedFromComputationOfDilutedNetLossPerCommonShareDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureNetLossPerShareAttributableToCommonStockholdersPotentialDilutiveSecuritiesExcludedFromComputationOfDilutedNetLossPerCommonShareDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EmployeeStockPurchasePlanMember" xlink:type="locator" xlink:label="sndx_EmployeeStockPurchasePlanMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_WarrantsToPurchaseCommonStockMember" xlink:type="locator" xlink:label="sndx_WarrantsToPurchaseCommonStockMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RestrictedStockUnitsRSUMember" xlink:type="locator" xlink:label="us-gaap_RestrictedStockUnitsRSUMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EmployeeStockOptionMember" xlink:type="locator" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:type="locator" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:to="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="us-gaap_AntidilutiveSecuritiesNameDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_RestrictedStockUnitsRSUMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="sndx_WarrantsToPurchaseCommonStockMember" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="sndx_EmployeeStockPurchasePlanMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" order="10180.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureNetLossPerShareAttributableToCommonStockholdersAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureNetLossPerShareAttributableToCommonStockholdersAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureNetLossPerShareAttributableToCommonStockholdersAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfWarrantOrRightOutstanding" xlink:type="locator" xlink:label="us-gaap_ClassOfWarrantOrRightOutstanding" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfPreFundedWarrantsExchangedForCommonStock" xlink:type="locator" xlink:label="sndx_NumberOfPreFundedWarrantsExchangedForCommonStock" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" xlink:type="locator" xlink:label="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SharesIssuedPricePerShare" xlink:type="locator" xlink:label="us-gaap_SharesIssuedPricePerShare" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" xlink:type="locator" xlink:label="us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ClassOfWarrantOrRightIssued" xlink:type="locator" xlink:label="sndx_ClassOfWarrantOrRightIssued" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfCommonStockWarrantsIssued" xlink:type="locator" xlink:label="sndx_NumberOfCommonStockWarrantsIssued" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfCommonStockConvertedToWarrants" xlink:type="locator" xlink:label="sndx_NumberOfCommonStockConvertedToWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PreFundedWarrantsMember" xlink:type="locator" xlink:label="sndx_PreFundedWarrantsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementEquityComponentsAxis" xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_BiotechnologyValueFundLPMember" xlink:type="locator" xlink:label="sndx_BiotechnologyValueFundLPMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CounterpartyNameAxis" xlink:type="locator" xlink:label="srt_CounterpartyNameAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EarningsPerShareBasicLineItems" xlink:type="locator" xlink:label="us-gaap_EarningsPerShareBasicLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" xlink:to="srt_CounterpartyNameAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_BiotechnologyValueFundLPMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfEarningsPerShareBasicByCommonClassTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="10100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_PreFundedWarrantsMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="sndx_NumberOfCommonStockConvertedToWarrants" order="10320.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="sndx_NumberOfCommonStockWarrantsIssued" order="10340.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="sndx_ClassOfWarrantOrRightIssued" order="10390.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" order="10430.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" order="10470.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_SharesIssuedPricePerShare" order="10510.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" order="10550.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="sndx_NumberOfPreFundedWarrantsExchangedForCommonStock" order="10590.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EarningsPerShareBasicLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightOutstanding" order="10630.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureSignificantAgreementsAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureSignificantAgreementsAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureSignificantAgreementsAdditionalInformationDetail">
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UpfrontLicenseFeesPaid" xlink:type="locator" xlink:label="sndx_UpfrontLicenseFeesPaid" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AccruedContractualObligation" xlink:type="locator" xlink:label="sndx_AccruedContractualObligation" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ContractualObligationsTerm" xlink:type="locator" xlink:label="sndx_ContractualObligationsTerm" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_RemainingContractualObligation" xlink:type="locator" xlink:label="sndx_RemainingContractualObligation" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ContractualObligation" xlink:type="locator" xlink:label="us-gaap_ContractualObligation" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_IncreaseDecreaseInContractualObligation" xlink:type="locator" xlink:label="sndx_IncreaseDecreaseInContractualObligation" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_MilestonePaymentDue" xlink:type="locator" xlink:label="sndx_MilestonePaymentDue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpense" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LicenseAgreementsExpirationPeriod" xlink:type="locator" xlink:label="sndx_LicenseAgreementsExpirationPeriod" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AggregatePotentialMilestonePayable" xlink:type="locator" xlink:label="sndx_AggregatePotentialMilestonePayable" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PotentialMilestonePaymentsUponAchievementOfMilestone" xlink:type="locator" xlink:label="sndx_PotentialMilestonePaymentsUponAchievementOfMilestone" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UpfrontPayments" xlink:type="locator" xlink:label="sndx_UpfrontPayments" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_BayerPharmaAgMember" xlink:type="locator" xlink:label="sndx_BayerPharmaAgMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LicenseAgreementMember" xlink:type="locator" xlink:label="sndx_LicenseAgreementMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EasternCooperativeOncologyGroupMember" xlink:type="locator" xlink:label="sndx_EasternCooperativeOncologyGroupMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ClinicalTrialMember" xlink:type="locator" xlink:label="sndx_ClinicalTrialMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UCBBiopharmaMember" xlink:type="locator" xlink:label="sndx_UCBBiopharmaMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_UcbLicenseAgreementMember" xlink:type="locator" xlink:label="sndx_UcbLicenseAgreementMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_VitaePharmaceuticalsIncMember" xlink:type="locator" xlink:label="sndx_VitaePharmaceuticalsIncMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CounterpartyNameAxis" xlink:type="locator" xlink:label="srt_CounterpartyNameAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AllerganLicenseAgreementMember" xlink:type="locator" xlink:label="sndx_AllerganLicenseAgreementMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:type="locator" xlink:label="us-gaap_ArrangementsAndNonarrangementTransactionsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_TypeOfArrangementAxis" xlink:type="locator" xlink:label="us-gaap_TypeOfArrangementAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:type="locator" xlink:label="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:to="us-gaap_TypeOfArrangementAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_TypeOfArrangementAxis" xlink:to="us-gaap_ArrangementsAndNonarrangementTransactionsMember" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:to="sndx_AllerganLicenseAgreementMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:to="srt_CounterpartyNameAxis" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_VitaePharmaceuticalsIncMember" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:to="sndx_UcbLicenseAgreementMember" order="10490.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_UCBBiopharmaMember" order="10610.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:to="sndx_ClinicalTrialMember" order="10890.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_EasternCooperativeOncologyGroupMember" order="11070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:to="sndx_LicenseAgreementMember" order="11250.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_BayerPharmaAgMember" order="11350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:to="srt_RangeAxis" order="11400.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="11430.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="11450.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="11470.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_UpfrontPayments" order="11500.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_PotentialMilestonePaymentsUponAchievementOfMilestone" order="11520.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_AggregatePotentialMilestonePayable" order="11540.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_LicenseAgreementsExpirationPeriod" order="11560.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_ResearchAndDevelopmentExpense" order="11610.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_MilestonePaymentDue" order="11980.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_IncreaseDecreaseInContractualObligation" order="12020.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_ContractualObligation" order="12060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_RemainingContractualObligation" order="12100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_ContractualObligationsTerm" order="12140.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_AccruedContractualObligation" order="12180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sndx_UpfrontLicenseFeesPaid" order="12290.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosurePropertyAndEquipmentNetPropertyAndEquipmentNetDetail" xlink:href="sndx-20201231.xsd#Role_DisclosurePropertyAndEquipmentNetPropertyAndEquipmentNetDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosurePropertyAndEquipmentNetPropertyAndEquipmentNetDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentNet" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" xlink:type="locator" xlink:label="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentGross" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentGross" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_OfficeEquipmentMember" xlink:type="locator" xlink:label="us-gaap_OfficeEquipmentMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ComputerAndOfficeEquipmentMember" xlink:type="locator" xlink:label="sndx_ComputerAndOfficeEquipmentMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FurnitureAndFixturesMember" xlink:type="locator" xlink:label="us-gaap_FurnitureAndFixturesMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LeaseholdImprovementsMember" xlink:type="locator" xlink:label="us-gaap_LeaseholdImprovementsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EquipmentMember" xlink:type="locator" xlink:label="us-gaap_EquipmentMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentTypeDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentByTypeAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PropertyPlantAndEquipmentLineItems" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" order="10030.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfPropertyPlantAndEquipmentTable" xlink:to="us-gaap_PropertyPlantAndEquipmentByTypeAxis" order="10060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain_2" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:to="us-gaap_PropertyPlantAndEquipmentTypeDomain" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_EquipmentMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_LeaseholdImprovementsMember" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_FurnitureAndFixturesMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="sndx_ComputerAndOfficeEquipmentMember" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:to="us-gaap_OfficeEquipmentMember" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentGross" order="10220.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" order="10460.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PropertyPlantAndEquipmentLineItems" xlink:to="us-gaap_PropertyPlantAndEquipmentNet" order="10500.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureFairValueMeasurementsScheduleOfFairValuesOfFinancialAssetsAndLiabilitiesMeasuredAtFairValueDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureFairValueMeasurementsScheduleOfFairValuesOfFinancialAssetsAndLiabilitiesMeasuredAtFairValueDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureFairValueMeasurementsScheduleOfFairValuesOfFinancialAssetsAndLiabilitiesMeasuredAtFairValueDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AssetsFairValueDisclosure" xlink:type="locator" xlink:label="us-gaap_AssetsFairValueDisclosure" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShortTermInvestments" xlink:type="locator" xlink:label="us-gaap_ShortTermInvestments" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CashAndCashEquivalentsFairValueDisclosure" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsFairValueDisclosure" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CarryingReportedAmountFairValueDisclosureMember" xlink:type="locator" xlink:label="us-gaap_CarryingReportedAmountFairValueDisclosureMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueDisclosureItemAmountsDomain" xlink:type="locator" xlink:label="us-gaap_FairValueDisclosureItemAmountsDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PortionAtFairValueFairValueDisclosureMember" xlink:type="locator" xlink:label="us-gaap_PortionAtFairValueFairValueDisclosureMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueByMeasurementBasisAxis" xlink:type="locator" xlink:label="us-gaap_FairValueByMeasurementBasisAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueInputsLevel3Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel3Member" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueInputsLevel2Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel2Member" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueInputsLevel1Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel1Member" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:type="locator" xlink:label="us-gaap_FairValueByFairValueHierarchyLevelAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" order="10030.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" xlink:to="us-gaap_FairValueByFairValueHierarchyLevelAxis" order="10060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain_2" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel1Member" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel2Member" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel3Member" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisTable" xlink:to="us-gaap_FairValueByMeasurementBasisAxis" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FairValueByMeasurementBasisAxis" xlink:to="us-gaap_PortionAtFairValueFairValueDisclosureMember" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueDisclosureItemAmountsDomain" xlink:to="us-gaap_PortionAtFairValueFairValueDisclosureMember" order="10180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByMeasurementBasisAxis" xlink:to="us-gaap_FairValueDisclosureItemAmountsDomain" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueDisclosureItemAmountsDomain" xlink:to="us-gaap_CarryingReportedAmountFairValueDisclosureMember" order="10230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_CashAndCashEquivalentsFairValueDisclosure" order="10260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_ShortTermInvestments" order="10360.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsAndLiabilitiesMeasuredOnRecurringAndNonrecurringBasisLineItems" xlink:to="us-gaap_AssetsFairValueDisclosure" order="10460.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureFairValueMeasurementsAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureFairValueMeasurementsAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureFairValueMeasurementsAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtSecuritiesAvailableForSaleRealizedGainLoss" xlink:type="locator" xlink:label="us-gaap_DebtSecuritiesAvailableForSaleRealizedGainLoss" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecurities" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleSecuritiesDebtSecurities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CashAndCashEquivalentsFairValueDisclosure" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsFairValueDisclosure" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShortTermInvestmentsMember" xlink:type="locator" xlink:label="us-gaap_ShortTermInvestmentsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_InvestmentTypeCategorizationMember" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeCategorizationMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_InvestmentTypeCategorizationMember" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeCategorizationMember_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_InvestmentTypeAxis" xlink:type="locator" xlink:label="us-gaap_InvestmentTypeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_CorporateBondsCommercialPaperCreditCardAssetBackSecuritiesAndUSTreasuriesMember" xlink:type="locator" xlink:label="sndx_CorporateBondsCommercialPaperCreditCardAssetBackSecuritiesAndUSTreasuriesMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_CorporateBondsAndCommercialPaperMember" xlink:type="locator" xlink:label="sndx_CorporateBondsAndCommercialPaperMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueByAssetClassAxis" xlink:type="locator" xlink:label="us-gaap_FairValueByAssetClassAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_OvernightInvestmentsAndMoneyMarketFundsMember" xlink:type="locator" xlink:label="sndx_OvernightInvestmentsAndMoneyMarketFundsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CashAndCashEquivalentsAxis" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueInputsLevel2Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel2Member" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueInputsLevel1Member" xlink:type="locator" xlink:label="us-gaap_FairValueInputsLevel1Member" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:type="locator" xlink:label="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:type="locator" xlink:label="us-gaap_FairValueByFairValueHierarchyLevelAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FairValueMeasurementsTable" xlink:type="locator" xlink:label="sndx_FairValueMeasurementsTable" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FairValueMeasurementsLineItems" xlink:type="locator" xlink:label="sndx_FairValueMeasurementsLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="sndx_FairValueMeasurementsLineItems" xlink:to="sndx_FairValueMeasurementsTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_FairValueMeasurementsTable" xlink:to="us-gaap_FairValueByFairValueHierarchyLevelAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByFairValueHierarchyLevelAxis" xlink:to="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel1Member" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueMeasurementsFairValueHierarchyDomain" xlink:to="us-gaap_FairValueInputsLevel2Member" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_FairValueMeasurementsTable" xlink:to="us-gaap_CashAndCashEquivalentsAxis" order="10120.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_CashAndCashEquivalentsAxis" xlink:to="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember_2" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_CashAndCashEquivalentsAxis" xlink:to="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RestrictedCashAndCashEquivalentsCashAndCashEquivalentsMember" xlink:to="sndx_OvernightInvestmentsAndMoneyMarketFundsMember" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_FairValueMeasurementsTable" xlink:to="us-gaap_FairValueByAssetClassAxis" order="10180.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_FairValueByAssetClassAxis" xlink:to="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain_2" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByAssetClassAxis" xlink:to="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:to="sndx_CorporateBondsAndCommercialPaperMember" order="10230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:to="sndx_CorporateBondsCommercialPaperCreditCardAssetBackSecuritiesAndUSTreasuriesMember" order="10350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_FairValueMeasurementsTable" xlink:to="us-gaap_InvestmentTypeAxis" order="10360.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_InvestmentTypeAxis" xlink:to="us-gaap_InvestmentTypeCategorizationMember_2" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_InvestmentTypeAxis" xlink:to="us-gaap_InvestmentTypeCategorizationMember" order="10390.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_InvestmentTypeCategorizationMember" xlink:to="us-gaap_ShortTermInvestmentsMember" order="10410.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_FairValueMeasurementsLineItems" xlink:to="us-gaap_CashAndCashEquivalentsFairValueDisclosure" order="10440.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_FairValueMeasurementsLineItems" xlink:to="us-gaap_AvailableForSaleSecuritiesDebtSecurities" order="10550.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_FairValueMeasurementsLineItems" xlink:to="us-gaap_DebtSecuritiesAvailableForSaleRealizedGainLoss" order="10620.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureFairValueMeasurementsSummaryOfAvailableForSaleSecuritiesDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureFairValueMeasurementsSummaryOfAvailableForSaleSecuritiesDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureFairValueMeasurementsSummaryOfAvailableForSaleSecuritiesDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecurities" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleSecuritiesDebtSecurities" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AssetBackedSecuritiesMember" xlink:type="locator" xlink:label="us-gaap_AssetBackedSecuritiesMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_USTreasurySecuritiesMember" xlink:type="locator" xlink:label="us-gaap_USTreasurySecuritiesMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CorporateDebtSecuritiesMember" xlink:type="locator" xlink:label="us-gaap_CorporateDebtSecuritiesMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommercialPaperNotIncludedWithCashAndCashEquivalentsMember" xlink:type="locator" xlink:label="us-gaap_CommercialPaperNotIncludedWithCashAndCashEquivalentsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:type="locator" xlink:label="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_FairValueByAssetClassAxis" xlink:type="locator" xlink:label="us-gaap_FairValueByAssetClassAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtSecuritiesAvailableForSaleTable" xlink:type="locator" xlink:label="us-gaap_DebtSecuritiesAvailableForSaleTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:type="locator" xlink:label="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_DebtSecuritiesAvailableForSaleTable" order="10040.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtSecuritiesAvailableForSaleTable" xlink:to="us-gaap_FairValueByAssetClassAxis" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_FairValueByAssetClassAxis" xlink:to="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" order="10100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:to="us-gaap_CommercialPaperNotIncludedWithCashAndCashEquivalentsMember" order="10120.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:to="us-gaap_CorporateDebtSecuritiesMember" order="10140.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:to="us-gaap_USTreasurySecuritiesMember" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_FairValueAssetsMeasuredOnRecurringBasisUnobservableInputReconciliationByAssetClassDomain" xlink:to="us-gaap_AssetBackedSecuritiesMember" order="10220.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" order="10250.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" order="10410.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" order="10570.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ScheduleOfAvailableForSaleSecuritiesLineItems" xlink:to="us-gaap_AvailableForSaleSecuritiesDebtSecurities" order="10730.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureCommonStockAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureCommonStockAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureCommonStockAdditionalInformationDetail">
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ExerciseOfWarrantsUpperLimitAfterExerciseAsPercentageOfCommonStock" xlink:type="locator" xlink:label="sndx_ExerciseOfWarrantsUpperLimitAfterExerciseAsPercentageOfCommonStock" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_WarrantExpirationTerm" xlink:type="locator" xlink:label="sndx_WarrantExpirationTerm" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfCommonStockWarrantsIssued" xlink:type="locator" xlink:label="sndx_NumberOfCommonStockWarrantsIssued" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfCommonStockConvertedToWarrants" xlink:type="locator" xlink:label="sndx_NumberOfCommonStockConvertedToWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_StockIssuedDuringPeriodSharesExerciseOfWarrants" xlink:type="locator" xlink:label="sndx_StockIssuedDuringPeriodSharesExerciseOfWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfWarrantsExercisedInCashlessExercise" xlink:type="locator" xlink:label="sndx_NumberOfWarrantsExercisedInCashlessExercise" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_WarrantsAndRightsOutstandingTerm" xlink:type="locator" xlink:label="us-gaap_WarrantsAndRightsOutstandingTerm" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_WarrantsAndRightsOutstandingMeasurementInput" xlink:type="locator" xlink:label="us-gaap_WarrantsAndRightsOutstandingMeasurementInput" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_FairValueOfWarrants" xlink:type="locator" xlink:label="sndx_FairValueOfWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_MaximumBeneficialOwnershipLimitationPercentage" xlink:type="locator" xlink:label="sndx_MaximumBeneficialOwnershipLimitationPercentage" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ExerciseOfWarrantsLowerLimitAfterExerciseAsPercentageOfCommonStock" xlink:type="locator" xlink:label="sndx_ExerciseOfWarrantsLowerLimitAfterExerciseAsPercentageOfCommonStock" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_MaximumPeriodAllowedToIncreaseBeneficialOwnershipLimitationAfterNotice" xlink:type="locator" xlink:label="sndx_MaximumPeriodAllowedToIncreaseBeneficialOwnershipLimitationAfterNotice" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfPreFundedWarrantsExchangedForCommonStock" xlink:type="locator" xlink:label="sndx_NumberOfPreFundedWarrantsExchangedForCommonStock" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfWarrantOrRightOutstanding" xlink:type="locator" xlink:label="us-gaap_ClassOfWarrantOrRightOutstanding" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockParOrStatedValuePerShare" xlink:type="locator" xlink:label="us-gaap_CommonStockParOrStatedValuePerShare" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AdjustedWeightedAverageExercisePriceOfWarrants" xlink:type="locator" xlink:label="sndx_AdjustedWeightedAverageExercisePriceOfWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_WeightedAverageExercisePriceOfWarrants" xlink:type="locator" xlink:label="sndx_WeightedAverageExercisePriceOfWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_OfferingCost" xlink:type="locator" xlink:label="sndx_OfferingCost" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_GrossProceedsFromOffering" xlink:type="locator" xlink:label="sndx_GrossProceedsFromOffering" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_OfferingPricePerShare" xlink:type="locator" xlink:label="sndx_OfferingPricePerShare" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ClassOfWarrantOrRightTerm" xlink:type="locator" xlink:label="sndx_ClassOfWarrantOrRightTerm" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" xlink:type="locator" xlink:label="us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" xlink:type="locator" xlink:label="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_NumberOfSeriesOfWarrants" xlink:type="locator" xlink:label="sndx_NumberOfSeriesOfWarrants" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PaymentSpecifiedPercentageOfGrossProceedsFromSaleOfShares" xlink:type="locator" xlink:label="sndx_PaymentSpecifiedPercentageOfGrossProceedsFromSaleOfShares" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_GrossProceedsFromIssuanceOfCommonStock" xlink:type="locator" xlink:label="sndx_GrossProceedsFromIssuanceOfCommonStock" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SaleOfStockPricePerShare" xlink:type="locator" xlink:label="us-gaap_SaleOfStockPricePerShare" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromIssuanceOfCommonStock" xlink:type="locator" xlink:label="us-gaap_ProceedsFromIssuanceOfCommonStock" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockSharesAuthorized" xlink:type="locator" xlink:label="us-gaap_CommonStockSharesAuthorized" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_BiotechnologyValueFundLPMember" xlink:type="locator" xlink:label="sndx_BiotechnologyValueFundLPMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:type="locator" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_CounterpartyNameAxis" xlink:type="locator" xlink:label="srt_CounterpartyNameAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_MeasurementInputOptionVolatilityMember" xlink:type="locator" xlink:label="us-gaap_MeasurementInputOptionVolatilityMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_MeasurementInputTypeDomain" xlink:type="locator" xlink:label="us-gaap_MeasurementInputTypeDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_MeasurementInputTypeDomain" xlink:type="locator" xlink:label="us-gaap_MeasurementInputTypeDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_MeasurementInputTypeAxis" xlink:type="locator" xlink:label="us-gaap_MeasurementInputTypeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SeriesOneAndSeriesTwoWarrantsMember" xlink:type="locator" xlink:label="sndx_SeriesOneAndSeriesTwoWarrantsMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SeriesTwoWarrantsMember" xlink:type="locator" xlink:label="sndx_SeriesTwoWarrantsMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SeriesOneWarrantsMember" xlink:type="locator" xlink:label="sndx_SeriesOneWarrantsMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SeriesWarrantsMember" xlink:type="locator" xlink:label="sndx_SeriesWarrantsMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PreFundedWarrantsMember" xlink:type="locator" xlink:label="sndx_PreFundedWarrantsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockMember" xlink:type="locator" xlink:label="us-gaap_CommonStockMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementEquityComponentsAxis" xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AtTheMarketEquityOfferingSalesAgreementMember" xlink:type="locator" xlink:label="sndx_AtTheMarketEquityOfferingSalesAgreementMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RelatedPartyTransactionDomain" xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RelatedPartyTransactionDomain" xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RelatedPartyTransactionAxis" xlink:type="locator" xlink:label="us-gaap_RelatedPartyTransactionAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_CowenAndCompanyLLCMember" xlink:type="locator" xlink:label="sndx_CowenAndCompanyLLCMember" />
    <link:loc xlink:href="https://xbrl.sec.gov/dei/2020/dei-2020-01-31.xsd#dei_EntityDomain" xlink:type="locator" xlink:label="dei_EntityDomain" />
    <link:loc xlink:href="https://xbrl.sec.gov/dei/2020/dei-2020-01-31.xsd#dei_EntityDomain" xlink:type="locator" xlink:label="dei_EntityDomain_2" />
    <link:loc xlink:href="https://xbrl.sec.gov/dei/2020/dei-2020-01-31.xsd#dei_LegalEntityAxis" xlink:type="locator" xlink:label="dei_LegalEntityAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IPOMember" xlink:type="locator" xlink:label="us-gaap_IPOMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:type="locator" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:type="locator" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfStockByClassTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfStockByClassTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfStockLineItems" xlink:type="locator" xlink:label="us-gaap_ClassOfStockLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ScheduleOfStockByClassTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="us-gaap_IPOMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="dei_LegalEntityAxis" order="10100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="dei_LegalEntityAxis" xlink:to="dei_EntityDomain_2" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="dei_LegalEntityAxis" xlink:to="dei_EntityDomain" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="dei_EntityDomain" xlink:to="sndx_CowenAndCompanyLLCMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_RelatedPartyTransactionAxis" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain_2" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RelatedPartyTransactionAxis" xlink:to="us-gaap_RelatedPartyTransactionDomain" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RelatedPartyTransactionDomain" xlink:to="sndx_AtTheMarketEquityOfferingSalesAgreementMember" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="srt_RangeAxis" order="10500.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10530.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10550.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10570.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="10580.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="10610.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" order="10630.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_PreFundedWarrantsMember" order="10650.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_SeriesWarrantsMember" order="10670.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_SeriesOneWarrantsMember" order="10810.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_SeriesTwoWarrantsMember" order="10830.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_SeriesOneAndSeriesTwoWarrantsMember" order="11450.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_MeasurementInputTypeAxis" order="11480.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_MeasurementInputTypeAxis" xlink:to="us-gaap_MeasurementInputTypeDomain_2" order="11490.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_MeasurementInputTypeAxis" xlink:to="us-gaap_MeasurementInputTypeDomain" order="11510.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_MeasurementInputTypeDomain" xlink:to="us-gaap_MeasurementInputOptionVolatilityMember" order="11530.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="srt_CounterpartyNameAxis" order="11540.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" order="11570.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sndx_BiotechnologyValueFundLPMember" order="11590.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_CommonStockSharesAuthorized" order="11760.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ProceedsFromIssuanceOfCommonStock" order="11810.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" order="11850.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_SaleOfStockPricePerShare" order="11890.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_GrossProceedsFromIssuanceOfCommonStock" order="11930.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_PaymentSpecifiedPercentageOfGrossProceedsFromSaleOfShares" order="12160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_NumberOfSeriesOfWarrants" order="12250.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" order="12270.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" order="12310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_ClassOfWarrantOrRightTerm" order="12330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_OfferingPricePerShare" order="12350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_GrossProceedsFromOffering" order="12390.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_OfferingCost" order="12410.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_WeightedAverageExercisePriceOfWarrants" order="12550.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_AdjustedWeightedAverageExercisePriceOfWarrants" order="12570.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_CommonStockParOrStatedValuePerShare" order="12640.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightOutstanding" order="12800.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_NumberOfPreFundedWarrantsExchangedForCommonStock" order="12820.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_MaximumPeriodAllowedToIncreaseBeneficialOwnershipLimitationAfterNotice" order="12910.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_ExerciseOfWarrantsLowerLimitAfterExerciseAsPercentageOfCommonStock" order="12930.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_MaximumBeneficialOwnershipLimitationPercentage" order="12950.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_FairValueOfWarrants" order="13020.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_WarrantsAndRightsOutstandingMeasurementInput" order="13040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_WarrantsAndRightsOutstandingTerm" order="13060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_NumberOfWarrantsExercisedInCashlessExercise" order="13080.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_StockIssuedDuringPeriodSharesExerciseOfWarrants" order="13100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_NumberOfCommonStockConvertedToWarrants" order="13150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_NumberOfCommonStockWarrantsIssued" order="13210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_WarrantExpirationTerm" order="13330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sndx_ExerciseOfWarrantsUpperLimitAfterExerciseAsPercentageOfCommonStock" order="13390.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureCommonStockScheduleOfCommonStockReservedForFutureIssuanceDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureCommonStockScheduleOfCommonStockReservedForFutureIssuanceDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureCommonStockScheduleOfCommonStockReservedForFutureIssuanceDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" xlink:type="locator" xlink:label="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PreFundedWarrantsMember" xlink:type="locator" xlink:label="sndx_PreFundedWarrantsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EquityComponentDomain" xlink:type="locator" xlink:label="us-gaap_EquityComponentDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StatementEquityComponentsAxis" xlink:type="locator" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EmployeeStockPurchasePlanMember" xlink:type="locator" xlink:label="sndx_EmployeeStockPurchasePlanMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EmployeeStockOptionMember" xlink:type="locator" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AwardTypeAxis" xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfStockByClassTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfStockByClassTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ClassOfStockLineItems" xlink:type="locator" xlink:label="us-gaap_ClassOfStockLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ScheduleOfStockByClassTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_AwardTypeAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sndx_EmployeeStockPurchasePlanMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_StatementEquityComponentsAxis" order="10120.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_EquityComponentDomain" xlink:to="sndx_PreFundedWarrantsMember" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" order="10200.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureStockBasedCompensationAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureStockBasedCompensationAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureStockBasedCompensationAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DefinedContributionPlanEmployerDiscretionaryContributionAmount" xlink:type="locator" xlink:label="us-gaap_DefinedContributionPlanEmployerDiscretionaryContributionAmount" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardOfferingPeriodDiscountRate" xlink:type="locator" xlink:label="sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardOfferingPeriodDiscountRate" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardPayrollDeductionsOfferingPeriod" xlink:type="locator" xlink:label="sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardPayrollDeductionsOfferingPeriod" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedWeightedAverageGrantDateFairValue" xlink:type="locator" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedWeightedAverageGrantDateFairValue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ProceedsFromStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_ProceedsFromStockOptionsExercised" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AllocatedShareBasedCompensationExpense" xlink:type="locator" xlink:label="us-gaap_AllocatedShareBasedCompensationExpense" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EmployeeServiceShareBasedCompensationRecognizedStockOptionsNotMet" xlink:type="locator" xlink:label="sndx_EmployeeServiceShareBasedCompensationRecognizedStockOptionsNotMet" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriod" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriod" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EmployeeServiceShareBasedCompensationRecognizedStockOptions" xlink:type="locator" xlink:label="sndx_EmployeeServiceShareBasedCompensationRecognizedStockOptions" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsVestedAndExpectedToVestOutstandingNumber" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsVestedAndExpectedToVestOutstandingNumber" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" xlink:type="locator" xlink:label="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" xlink:type="locator" xlink:label="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardAnnualIncreasePercentageInNumberOfSharesAvailableForGrant" xlink:type="locator" xlink:label="sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardAnnualIncreasePercentageInNumberOfSharesAvailableForGrant" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" xlink:type="locator" xlink:label="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EmployeeStockPurchasePlanMember" xlink:type="locator" xlink:label="sndx_EmployeeStockPurchasePlanMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RestrictedStockUnitsRSUMember" xlink:type="locator" xlink:label="us-gaap_RestrictedStockUnitsRSUMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_EmployeesMember" xlink:type="locator" xlink:label="sndx_EmployeesMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:type="locator" xlink:label="srt_TitleOfIndividualWithRelationshipToEntityDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:type="locator" xlink:label="srt_TitleOfIndividualWithRelationshipToEntityDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_TitleOfIndividualAxis" xlink:type="locator" xlink:label="srt_TitleOfIndividualAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_TwoThousandAndSevenStockIncentivePlanMember" xlink:type="locator" xlink:label="sndx_TwoThousandAndSevenStockIncentivePlanMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_ServiceBasedOptionsMember" xlink:type="locator" xlink:label="sndx_ServiceBasedOptionsMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PerformanceSharesMember" xlink:type="locator" xlink:label="us-gaap_PerformanceSharesMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AwardTypeAxis" xlink:type="locator" xlink:label="us-gaap_AwardTypeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_TwoThousandSevenAndTwoThousandFifteenStockIncentivePlanMember" xlink:type="locator" xlink:label="sndx_TwoThousandSevenAndTwoThousandFifteenStockIncentivePlanMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventMember" xlink:type="locator" xlink:label="us-gaap_SubsequentEventMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventTypeDomain" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_SubsequentEventTypeAxis" xlink:type="locator" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_TwoThousandFifteenOmnibusIncentivePlanMember" xlink:type="locator" xlink:label="sndx_TwoThousandFifteenOmnibusIncentivePlanMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PlanNameDomain" xlink:type="locator" xlink:label="us-gaap_PlanNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PlanNameDomain" xlink:type="locator" xlink:label="us-gaap_PlanNameDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PlanNameAxis" xlink:type="locator" xlink:label="us-gaap_PlanNameAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_PlanNameAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_PlanNameAxis" xlink:to="us-gaap_PlanNameDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_PlanNameAxis" xlink:to="us-gaap_PlanNameDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="sndx_TwoThousandFifteenOmnibusIncentivePlanMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="srt_RangeAxis" order="10200.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10250.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10270.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_SubsequentEventTypeAxis" order="10280.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" order="10310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="sndx_TwoThousandSevenAndTwoThousandFifteenStockIncentivePlanMember" order="10390.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_AwardTypeAxis" order="10420.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" order="10450.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_PerformanceSharesMember" order="10470.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sndx_ServiceBasedOptionsMember" order="10490.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="sndx_TwoThousandAndSevenStockIncentivePlanMember" order="10750.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="srt_TitleOfIndividualAxis" order="10760.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="srt_TitleOfIndividualAxis" xlink:to="srt_TitleOfIndividualWithRelationshipToEntityDomain_2" order="10770.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_TitleOfIndividualAxis" xlink:to="srt_TitleOfIndividualWithRelationshipToEntityDomain" order="10790.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:to="sndx_EmployeesMember" order="10810.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_RestrictedStockUnitsRSUMember" order="11150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_PlanNameDomain" xlink:to="sndx_EmployeeStockPurchasePlanMember" order="11270.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" order="11640.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" order="11660.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardAnnualIncreasePercentageInNumberOfSharesAvailableForGrant" order="11710.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedStockOptions" order="11820.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" order="11840.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" order="11930.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsVestedAndExpectedToVestOutstandingNumber" order="11990.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsForfeituresInPeriod" order="12050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="sndx_EmployeeServiceShareBasedCompensationRecognizedStockOptions" order="12170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriod" order="12260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="sndx_EmployeeServiceShareBasedCompensationRecognizedStockOptionsNotMet" order="12490.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_AllocatedShareBasedCompensationExpense" order="12640.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageGrantDateFairValue" order="12690.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingPeriod1" order="12790.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" order="12940.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ProceedsFromStockOptionsExercised" order="13000.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisesInPeriodTotalIntrinsicValue" order="13060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardOptionsNonvestedOptionsForfeitedWeightedAverageGrantDateFairValue" order="13210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfAdditionalSharesAuthorized" order="13260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesEmployeeStockPurchasePlans" order="13300.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardPayrollDeductionsOfferingPeriod" order="13380.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="sndx_ShareBasedCompensationArrangementByShareBasedPaymentAwardOfferingPeriodDiscountRate" order="13420.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_DefinedContributionPlanEmployerDiscretionaryContributionAmount" order="13580.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureStockBasedCompensationShareBasedCompensationExpenseRelatedToIssuanceOfStockOptionAwardsToEmployeesAndNonEmployeesRelatedToEmployeeStockPurchasePlanDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureStockBasedCompensationShareBasedCompensationExpenseRelatedToIssuanceOfStockOptionAwardsToEmployeesAndNonEmployeesRelatedToEmployeeStockPurchasePlanDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureStockBasedCompensationShareBasedCompensationExpenseRelatedToIssuanceOfStockOptionAwardsToEmployeesAndNonEmployeesRelatedToEmployeeStockPurchasePlanDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_AllocatedShareBasedCompensationExpense" xlink:type="locator" xlink:label="us-gaap_AllocatedShareBasedCompensationExpense" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_GeneralAndAdministrativeExpenseMember" xlink:type="locator" xlink:label="us-gaap_GeneralAndAdministrativeExpenseMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ResearchAndDevelopmentExpenseMember" xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpenseMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeStatementLocationDomain" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeStatementLocationDomain" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeStatementLocationAxis" xlink:type="locator" xlink:label="us-gaap_IncomeStatementLocationAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:type="locator" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_IncomeStatementLocationAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_ResearchAndDevelopmentExpenseMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_GeneralAndAdministrativeExpenseMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_AllocatedShareBasedCompensationExpense" order="10140.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureLoanPayableAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureLoanPayableAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureLoanPayableAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_InterestExpense" xlink:type="locator" xlink:label="us-gaap_InterestExpense" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AdditionalDefaultInterestRate" xlink:type="locator" xlink:label="sndx_AdditionalDefaultInterestRate" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LineOfCreditFacilityMinimumCashCovenantWaived" xlink:type="locator" xlink:label="sndx_LineOfCreditFacilityMinimumCashCovenantWaived" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LineOfCreditFacilityMinimumCashCovenant" xlink:type="locator" xlink:label="sndx_LineOfCreditFacilityMinimumCashCovenant" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PercentageOfRepaymentOnAggregatePrincipalAmountOfTermLoanAdvances" xlink:type="locator" xlink:label="sndx_PercentageOfRepaymentOnAggregatePrincipalAmountOfTermLoanAdvances" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PaymentOfFacilityCharges" xlink:type="locator" xlink:label="sndx_PaymentOfFacilityCharges" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingThereafter" xlink:type="locator" xlink:label="sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingThereafter" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingInSecondYear" xlink:type="locator" xlink:label="sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingInSecondYear" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingInFirstYear" xlink:type="locator" xlink:label="sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingInFirstYear" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentMaturityDate" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentMaturityDate" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentInterestRateEffectivePercentage" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentInterestRateEffectivePercentage" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentBasisSpreadOnVariableRate1" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentBasisSpreadOnVariableRate1" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentInterestRateStatedPercentage" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentInterestRateStatedPercentage" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LineOfCreditFacilityInterestRateDescription" xlink:type="locator" xlink:label="us-gaap_LineOfCreditFacilityInterestRateDescription" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LineOfCreditFacilityElectedNotToDraw" xlink:type="locator" xlink:label="sndx_LineOfCreditFacilityElectedNotToDraw" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity" xlink:type="locator" xlink:label="us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_DebtInstrumentTrancheTwoMember" xlink:type="locator" xlink:label="sndx_DebtInstrumentTrancheTwoMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PrimeRateMember" xlink:type="locator" xlink:label="us-gaap_PrimeRateMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_VariableRateDomain" xlink:type="locator" xlink:label="us-gaap_VariableRateDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_VariableRateDomain" xlink:type="locator" xlink:label="us-gaap_VariableRateDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_VariableRateAxis" xlink:type="locator" xlink:label="us-gaap_VariableRateAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MaximumMember" xlink:type="locator" xlink:label="srt_MaximumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_MinimumMember" xlink:type="locator" xlink:label="srt_MinimumMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeMember" xlink:type="locator" xlink:label="srt_RangeMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/srt/2020/elts/srt-2020-01-31.xsd#srt_RangeAxis" xlink:type="locator" xlink:label="srt_RangeAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_AdditionalTermLoanMember" xlink:type="locator" xlink:label="sndx_AdditionalTermLoanMember" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_TermLoanMember" xlink:type="locator" xlink:label="sndx_TermLoanMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentNameDomain" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentNameDomain" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentNameDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentAxis" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_LoanAndSecurityAgreementMember" xlink:type="locator" xlink:label="sndx_LoanAndSecurityAgreementMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CreditFacilityDomain" xlink:type="locator" xlink:label="us-gaap_CreditFacilityDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CreditFacilityDomain" xlink:type="locator" xlink:label="us-gaap_CreditFacilityDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_CreditFacilityAxis" xlink:type="locator" xlink:label="us-gaap_CreditFacilityAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_HerculesCapitalIncMember" xlink:type="locator" xlink:label="sndx_HerculesCapitalIncMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LineOfCreditFacilityLenderDomain" xlink:type="locator" xlink:label="us-gaap_LineOfCreditFacilityLenderDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LineOfCreditFacilityLenderDomain" xlink:type="locator" xlink:label="us-gaap_LineOfCreditFacilityLenderDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_LineOfCreditFacilityAxis" xlink:type="locator" xlink:label="us-gaap_LineOfCreditFacilityAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentTable" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentTable" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DebtInstrumentLineItems" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_LineOfCreditFacilityAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_LineOfCreditFacilityAxis" xlink:to="us-gaap_LineOfCreditFacilityLenderDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_LineOfCreditFacilityAxis" xlink:to="us-gaap_LineOfCreditFacilityLenderDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_LineOfCreditFacilityLenderDomain" xlink:to="sndx_HerculesCapitalIncMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_CreditFacilityAxis" order="10100.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_CreditFacilityAxis" xlink:to="us-gaap_CreditFacilityDomain_2" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_CreditFacilityAxis" xlink:to="us-gaap_CreditFacilityDomain" order="10130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_CreditFacilityDomain" xlink:to="sndx_LoanAndSecurityAgreementMember" order="10150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_DebtInstrumentAxis" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_DebtInstrumentAxis" xlink:to="us-gaap_DebtInstrumentNameDomain_2" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_DebtInstrumentAxis" xlink:to="us-gaap_DebtInstrumentNameDomain" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentNameDomain" xlink:to="sndx_TermLoanMember" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentNameDomain" xlink:to="sndx_AdditionalTermLoanMember" order="10230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="srt_RangeAxis" order="10260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" order="10290.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MinimumMember" order="10310.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_VariableRateAxis" order="10340.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_VariableRateAxis" xlink:to="us-gaap_VariableRateDomain_2" order="10350.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_VariableRateAxis" xlink:to="us-gaap_VariableRateDomain" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_VariableRateDomain" xlink:to="us-gaap_PrimeRateMember" order="10390.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentNameDomain" xlink:to="sndx_DebtInstrumentTrancheTwoMember" order="10650.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_LineOfCreditFacilityMaximumBorrowingCapacity" order="10920.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_LineOfCreditFacilityElectedNotToDraw" order="10980.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_LineOfCreditFacilityInterestRateDescription" order="11000.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentInterestRateStatedPercentage" order="11020.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentBasisSpreadOnVariableRate1" order="11040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentInterestRateEffectivePercentage" order="11060.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentMaturityDate" order="11110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingInFirstYear" order="11130.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingInSecondYear" order="11150.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_PercentageOfPrepaymentPremiumOfPrincipalAmountOutstandingThereafter" order="11170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_PaymentOfFacilityCharges" order="11190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_PercentageOfRepaymentOnAggregatePrincipalAmountOfTermLoanAdvances" order="11230.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_LineOfCreditFacilityMinimumCashCovenant" order="11280.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_LineOfCreditFacilityMinimumCashCovenantWaived" order="11300.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sndx_AdditionalDefaultInterestRate" order="11320.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_InterestExpense" order="11370.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureIncomeTaxesAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureIncomeTaxesAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureIncomeTaxesAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate" xlink:type="locator" xlink:label="us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense" xlink:type="locator" xlink:label="us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_UnrecognizedTaxBenefitsPeriodIncreaseDecrease" xlink:type="locator" xlink:label="us-gaap_UnrecognizedTaxBenefitsPeriodIncreaseDecrease" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_DeferredTaxAssetsResearchCreditsExpirationPeriod" xlink:type="locator" xlink:label="sndx_DeferredTaxAssetsResearchCreditsExpirationPeriod" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DeferredTaxAssetsTaxCreditCarryforwardsResearch" xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsTaxCreditCarryforwardsResearch" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_DeferredTaxAssetsOperatingLossCarryforwardsExpirationPeriod" xlink:type="locator" xlink:label="sndx_DeferredTaxAssetsOperatingLossCarryforwardsExpirationPeriod" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsStateAndLocal" xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsStateAndLocal" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsDomestic" xlink:type="locator" xlink:label="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsDomestic" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ValuationAllowanceMethodologiesAndAssumptions" xlink:type="locator" xlink:label="us-gaap_ValuationAllowanceMethodologiesAndAssumptions" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_ValuationAllowanceDeferredTaxAssetChangeInAmount" xlink:type="locator" xlink:label="us-gaap_ValuationAllowanceDeferredTaxAssetChangeInAmount" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:type="locator" xlink:label="us-gaap_IncomeTaxExpenseBenefit" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_InternalRevenueServiceIRSMember" xlink:type="locator" xlink:label="us-gaap_InternalRevenueServiceIRSMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxAuthorityNameDomain" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityNameDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxAuthorityNameDomain" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityNameDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxAuthorityNameAxis" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityNameAxis" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_StateAndLocalJurisdictionMember" xlink:type="locator" xlink:label="us-gaap_StateAndLocalJurisdictionMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_DomesticCountryMember" xlink:type="locator" xlink:label="us-gaap_DomesticCountryMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxAuthorityDomain" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxAuthorityDomain" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_IncomeTaxAuthorityAxis" xlink:type="locator" xlink:label="us-gaap_IncomeTaxAuthorityAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_IncomeTaxesTable" xlink:type="locator" xlink:label="sndx_IncomeTaxesTable" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_IncomeTaxesLineItems" xlink:type="locator" xlink:label="sndx_IncomeTaxesLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="sndx_IncomeTaxesTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_IncomeTaxesTable" xlink:to="us-gaap_IncomeTaxAuthorityAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_IncomeTaxAuthorityAxis" xlink:to="us-gaap_IncomeTaxAuthorityDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeTaxAuthorityAxis" xlink:to="us-gaap_IncomeTaxAuthorityDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxAuthorityDomain" xlink:to="us-gaap_DomesticCountryMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxAuthorityDomain" xlink:to="us-gaap_StateAndLocalJurisdictionMember" order="10110.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_IncomeTaxesTable" xlink:to="us-gaap_IncomeTaxAuthorityNameAxis" order="10160.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_IncomeTaxAuthorityNameAxis" xlink:to="us-gaap_IncomeTaxAuthorityNameDomain_2" order="10170.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_IncomeTaxAuthorityNameAxis" xlink:to="us-gaap_IncomeTaxAuthorityNameDomain" order="10190.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_IncomeTaxAuthorityNameDomain" xlink:to="us-gaap_InternalRevenueServiceIRSMember" order="10210.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_IncomeTaxExpenseBenefit" order="10260.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_ValuationAllowanceDeferredTaxAssetChangeInAmount" order="10330.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_ValuationAllowanceMethodologiesAndAssumptions" order="10370.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsDomestic" order="10440.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_DeferredTaxAssetsOperatingLossCarryforwardsStateAndLocal" order="10460.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="sndx_DeferredTaxAssetsOperatingLossCarryforwardsExpirationPeriod" order="10480.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_DeferredTaxAssetsTaxCreditCarryforwardsResearch" order="10500.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="sndx_DeferredTaxAssetsResearchCreditsExpirationPeriod" order="10540.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_UnrecognizedTaxBenefitsPeriodIncreaseDecrease" order="10610.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_UnrecognizedTaxBenefitsIncomeTaxPenaltiesAndInterestExpense" order="10650.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_IncomeTaxesLineItems" xlink:to="us-gaap_UnrecognizedTaxBenefitsThatWouldImpactEffectiveTaxRate" order="10690.00" priority="2" use="optional" />
  </link:definitionLink>
  <link:roleRef roleURI="http://www.syndax.com/20201231/taxonomy/role/DisclosureCommitmentsAdditionalInformationDetail" xlink:href="sndx-20201231.xsd#Role_DisclosureCommitmentsAdditionalInformationDetail" xlink:type="simple" />
  <link:definitionLink xlink:type="extended" xlink:role="http://www.syndax.com/20201231/taxonomy/role/DisclosureCommitmentsAdditionalInformationDetail">
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_PurchaseObligation" xlink:type="locator" xlink:label="us-gaap_PurchaseObligation" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_SeriesB1PurchaseAgreementMember" xlink:type="locator" xlink:label="sndx_SeriesB1PurchaseAgreementMember" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RegistrationPaymentArrangementArrangementDomain" xlink:type="locator" xlink:label="us-gaap_RegistrationPaymentArrangementArrangementDomain" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RegistrationPaymentArrangementArrangementDomain" xlink:type="locator" xlink:label="us-gaap_RegistrationPaymentArrangementArrangementDomain_2" />
    <link:loc xlink:href="http://xbrl.fasb.org/us-gaap/2020/elts/us-gaap-2020-01-31.xsd#us-gaap_RegistrationPaymentArrangementByArrangementAxis" xlink:type="locator" xlink:label="us-gaap_RegistrationPaymentArrangementByArrangementAxis" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_CommitmentAndContingenciesTable" xlink:type="locator" xlink:label="sndx_CommitmentAndContingenciesTable" />
    <link:loc xlink:href="sndx-20201231.xsd#sndx_CommitmentAndContingenciesLineItems" xlink:type="locator" xlink:label="sndx_CommitmentAndContingenciesLineItems" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="sndx_CommitmentAndContingenciesLineItems" xlink:to="sndx_CommitmentAndContingenciesTable" order="10010.00" priority="2" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="sndx_CommitmentAndContingenciesTable" xlink:to="us-gaap_RegistrationPaymentArrangementByArrangementAxis" order="10040.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="us-gaap_RegistrationPaymentArrangementByArrangementAxis" xlink:to="us-gaap_RegistrationPaymentArrangementArrangementDomain_2" order="10050.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="us-gaap_RegistrationPaymentArrangementByArrangementAxis" xlink:to="us-gaap_RegistrationPaymentArrangementArrangementDomain" order="10070.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="us-gaap_RegistrationPaymentArrangementArrangementDomain" xlink:to="sndx_SeriesB1PurchaseAgreementMember" order="10090.00" priority="2" use="optional" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="sndx_CommitmentAndContingenciesLineItems" xlink:to="us-gaap_PurchaseObligation" order="10120.00" priority="2" use="optional" />
  </link:definitionLink>
</link:linkbase>
