<?xml version="1.0" encoding="UTF-8"?>

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2023 Workiva-->
<!--r:e5c40ce0-605c-42aa-88f6-cc4117781306,g:dbaa7cea-037e-40c6-bcfc-24fc5d4e4076-->
<link:linkbase xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/all" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain"/>
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member"/>
  <link:roleRef roleURI="http://www.ardelyx.com/role/Cover" xlink:type="simple" xlink:href="ardx-20230925.xsd#Cover"/>
  <link:definitionLink xlink:role="http://www.ardelyx.com/role/Cover" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressesLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentType_d105188d-45a3-43fe-bca9-6668380685ed" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentType"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_DocumentType_d105188d-45a3-43fe-bca9-6668380685ed" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentPeriodEndDate_d0ce1175-8411-47b3-8cff-5c3640c880a9" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_DocumentPeriodEndDate"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_DocumentPeriodEndDate_d0ce1175-8411-47b3-8cff-5c3640c880a9" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityRegistrantName_d1d7137e-f2b2-4969-a1a8-a5d52c000dc4" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityRegistrantName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityRegistrantName_d1d7137e-f2b2-4969-a1a8-a5d52c000dc4" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityCentralIndexKey_fe39d768-c87d-471d-afc3-2207b83d5bf5" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityCentralIndexKey"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityCentralIndexKey_fe39d768-c87d-471d-afc3-2207b83d5bf5" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AmendmentFlag_c007f36f-53e6-4b19-a951-f138867d1841" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AmendmentFlag"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_AmendmentFlag_c007f36f-53e6-4b19-a951-f138867d1841" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityIncorporationStateCountryCode_3ba1017d-d5fa-4d55-93b1-6bbcbf76c482" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityIncorporationStateCountryCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityIncorporationStateCountryCode_3ba1017d-d5fa-4d55-93b1-6bbcbf76c482" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityFileNumber_1f3bfab9-8075-472a-8af5-54b4afa24b97" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityFileNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityFileNumber_1f3bfab9-8075-472a-8af5-54b4afa24b97" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityTaxIdentificationNumber_7088dbfe-777a-42e3-8678-37e2615f69d6" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityTaxIdentificationNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityTaxIdentificationNumber_7088dbfe-777a-42e3-8678-37e2615f69d6" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine1_3717725f-ead7-4775-85da-cf823afbcaed" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressAddressLine1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityAddressAddressLine1_3717725f-ead7-4775-85da-cf823afbcaed" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine2_f2c96947-8f2e-499f-9113-f518c3d4e1c0" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressAddressLine2"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityAddressAddressLine2_f2c96947-8f2e-499f-9113-f518c3d4e1c0" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_e1d0d95f-c314-44a0-abe9-b4fd6f95ee40" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressCityOrTown"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityAddressCityOrTown_e1d0d95f-c314-44a0-abe9-b4fd6f95ee40" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_5ccda332-df4d-4865-acf2-66a168ff5b76" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressStateOrProvince"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityAddressStateOrProvince_5ccda332-df4d-4865-acf2-66a168ff5b76" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_f4c2ba97-ae97-4be4-a636-1a23f81c5e2c" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressPostalZipCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityAddressPostalZipCode_f4c2ba97-ae97-4be4-a636-1a23f81c5e2c" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CityAreaCode_01ad120f-7835-4052-90e6-62475eb0b9d0" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_CityAreaCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_CityAreaCode_01ad120f-7835-4052-90e6-62475eb0b9d0" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_LocalPhoneNumber_642b16f4-d00b-4c0d-9672-58a554602a0a" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_LocalPhoneNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_LocalPhoneNumber_642b16f4-d00b-4c0d-9672-58a554602a0a" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_WrittenCommunications_489d8b54-2d95-407d-abf9-1d774768bf39" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_WrittenCommunications"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_WrittenCommunications_489d8b54-2d95-407d-abf9-1d774768bf39" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SolicitingMaterial_77538e24-bcad-4bfb-8ae1-ce39e63d47a8" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_SolicitingMaterial"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_SolicitingMaterial_77538e24-bcad-4bfb-8ae1-ce39e63d47a8" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementTenderOffer_03a5acaa-f96a-43c6-a035-9ae9d784235a" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_PreCommencementTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_PreCommencementTenderOffer_03a5acaa-f96a-43c6-a035-9ae9d784235a" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementIssuerTenderOffer_658334c9-25af-47b1-aadb-f281e7f67ace" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_PreCommencementIssuerTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_PreCommencementIssuerTenderOffer_658334c9-25af-47b1-aadb-f281e7f67ace" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_Security12bTitle_1ad446c9-b5c3-4d0e-b759-baa9dff18ccf" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_Security12bTitle"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_Security12bTitle_1ad446c9-b5c3-4d0e-b759-baa9dff18ccf" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_TradingSymbol_5a38d765-454f-4795-99a5-2dd7de0aedf0" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_TradingSymbol"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_TradingSymbol_5a38d765-454f-4795-99a5-2dd7de0aedf0" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SecurityExchangeName_53ad6057-67b6-42f6-83a8-daa83bf2d7ad" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_SecurityExchangeName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_SecurityExchangeName_53ad6057-67b6-42f6-83a8-daa83bf2d7ad" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityEmergingGrowthCompany_2d9eec5e-7e44-40df-b7dc-934029fea09a" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityEmergingGrowthCompany"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityEmergingGrowthCompany_2d9eec5e-7e44-40df-b7dc-934029fea09a" xlink:type="arc" order="22"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesTable_cd6d0d6c-6512-4f29-aeee-0803b27b6ff6" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressesTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_dei_EntityAddressesLineItems_dcb35fa8-0a7c-4a9d-b19a-d614ef703f0c" xlink:to="loc_dei_EntityAddressesTable_cd6d0d6c-6512-4f29-aeee-0803b27b6ff6" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesAddressTypeAxis_fca12b82-790b-49ac-8d42-e2b680c2d9fb" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_EntityAddressesAddressTypeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_dei_EntityAddressesTable_cd6d0d6c-6512-4f29-aeee-0803b27b6ff6" xlink:to="loc_dei_EntityAddressesAddressTypeAxis_fca12b82-790b-49ac-8d42-e2b680c2d9fb" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_fca12b82-790b-49ac-8d42-e2b680c2d9fb_default" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AddressTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_dei_EntityAddressesAddressTypeAxis_fca12b82-790b-49ac-8d42-e2b680c2d9fb" xlink:to="loc_dei_AddressTypeDomain_fca12b82-790b-49ac-8d42-e2b680c2d9fb_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_9e2cd951-8ce7-4cba-9ce2-6ce2ab949f89" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_AddressTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_dei_EntityAddressesAddressTypeAxis_fca12b82-790b-49ac-8d42-e2b680c2d9fb" xlink:to="loc_dei_AddressTypeDomain_9e2cd951-8ce7-4cba-9ce2-6ce2ab949f89" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_OtherAddressMember_886afac1-3634-4037-b4f6-a61a1a7fda03" xlink:href="https://xbrl.sec.gov/dei/2022/dei-2022.xsd#dei_OtherAddressMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_AddressTypeDomain_9e2cd951-8ce7-4cba-9ce2-6ce2ab949f89" xlink:to="loc_dei_OtherAddressMember_886afac1-3634-4037-b4f6-a61a1a7fda03" xlink:type="arc" order="0"/>
  </link:definitionLink>
</link:linkbase>
