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

<!--XBRL Document Created with Wdesk from Workiva-->
<!--Copyright 2022 Workiva-->
<!--r:ff01a2df-e621-444b-be09-5a32db45a59d,g:e65bfb74-5f2f-479a-9fab-a937c254671f-->
<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-20220223.xsd#Cover"/>
  <link:definitionLink xlink:role="http://www.ardelyx.com/role/Cover" xlink:type="extended" id="ia2b3c98e545c4e4b81a39dcea501b6f7_Cover">
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressesLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentType_987a7f10-8498-4fd1-9fea-b7d6e0e27a9d" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentType"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_DocumentType_987a7f10-8498-4fd1-9fea-b7d6e0e27a9d" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentPeriodEndDate_d7ff01a9-8e75-43b0-97cc-928c8cedfe58" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_DocumentPeriodEndDate"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_DocumentPeriodEndDate_d7ff01a9-8e75-43b0-97cc-928c8cedfe58" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityRegistrantName_79c41aee-44aa-49da-b07a-2376e1b00b02" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityRegistrantName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityRegistrantName_79c41aee-44aa-49da-b07a-2376e1b00b02" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityCentralIndexKey_56d1ae4e-c1e4-45b2-acc4-aea2f350a277" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityCentralIndexKey"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityCentralIndexKey_56d1ae4e-c1e4-45b2-acc4-aea2f350a277" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AmendmentFlag_34b94660-1fe7-4722-910e-2b68eb0e5139" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_AmendmentFlag"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_AmendmentFlag_34b94660-1fe7-4722-910e-2b68eb0e5139" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityIncorporationStateCountryCode_3bd4a954-c36b-49e2-9f77-2a013fdf186a" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityIncorporationStateCountryCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityIncorporationStateCountryCode_3bd4a954-c36b-49e2-9f77-2a013fdf186a" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityFileNumber_b3d4ee6b-8260-4664-908e-fd0b55703f5e" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityFileNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityFileNumber_b3d4ee6b-8260-4664-908e-fd0b55703f5e" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityTaxIdentificationNumber_03ec88d3-ec0a-4945-9e09-8428ddbea38e" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityTaxIdentificationNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityTaxIdentificationNumber_03ec88d3-ec0a-4945-9e09-8428ddbea38e" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine1_34fd9231-76e2-4bce-b541-ffe91db96d07" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressAddressLine1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityAddressAddressLine1_34fd9231-76e2-4bce-b541-ffe91db96d07" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine2_91701dd2-f3e4-4f33-9f73-eaf0312a5970" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressAddressLine2"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityAddressAddressLine2_91701dd2-f3e4-4f33-9f73-eaf0312a5970" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_0abad869-b6ad-41b1-af81-a536b5d0e883" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressCityOrTown"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityAddressCityOrTown_0abad869-b6ad-41b1-af81-a536b5d0e883" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_41ba9a8d-7b21-4725-92d7-5a42b83f9627" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressStateOrProvince"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityAddressStateOrProvince_41ba9a8d-7b21-4725-92d7-5a42b83f9627" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_05724727-a849-4373-a2a2-01080f00e687" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressPostalZipCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityAddressPostalZipCode_05724727-a849-4373-a2a2-01080f00e687" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CityAreaCode_9285d9d1-17f7-4c63-bc96-a02f32504be9" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_CityAreaCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_CityAreaCode_9285d9d1-17f7-4c63-bc96-a02f32504be9" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_LocalPhoneNumber_7151412c-b4e3-45ac-ac4b-25a044a122a7" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_LocalPhoneNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_LocalPhoneNumber_7151412c-b4e3-45ac-ac4b-25a044a122a7" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_WrittenCommunications_e16f679b-6a14-4c10-a77f-dbdcc3e7f398" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_WrittenCommunications"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_WrittenCommunications_e16f679b-6a14-4c10-a77f-dbdcc3e7f398" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SolicitingMaterial_c61a6d06-cc75-41fa-a831-767403bf8463" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_SolicitingMaterial"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_SolicitingMaterial_c61a6d06-cc75-41fa-a831-767403bf8463" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementTenderOffer_cad60a47-9bfb-4c24-8955-e6c116e90445" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_PreCommencementTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_PreCommencementTenderOffer_cad60a47-9bfb-4c24-8955-e6c116e90445" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementIssuerTenderOffer_31da5c3f-81f5-4608-855b-7e397c180502" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_PreCommencementIssuerTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_PreCommencementIssuerTenderOffer_31da5c3f-81f5-4608-855b-7e397c180502" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_Security12bTitle_6d3e6410-1dc0-4c16-945d-12218b444628" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_Security12bTitle"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_Security12bTitle_6d3e6410-1dc0-4c16-945d-12218b444628" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_TradingSymbol_45e138c9-8da1-474e-ae72-6f157d6ae3c5" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_TradingSymbol"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_TradingSymbol_45e138c9-8da1-474e-ae72-6f157d6ae3c5" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SecurityExchangeName_374c943d-8126-4b6f-9410-a192a40ea54d" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_SecurityExchangeName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_SecurityExchangeName_374c943d-8126-4b6f-9410-a192a40ea54d" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityEmergingGrowthCompany_8676b60c-1c53-49d7-8d1a-5cfd22627b9b" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityEmergingGrowthCompany"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityEmergingGrowthCompany_8676b60c-1c53-49d7-8d1a-5cfd22627b9b" xlink:type="arc" order="22"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesTable_4f7d0307-09d4-4427-b674-60d142c64a5b" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressesTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_dei_EntityAddressesLineItems_15a4e4c6-95b0-4ea7-919f-1e4834458654" xlink:to="loc_dei_EntityAddressesTable_4f7d0307-09d4-4427-b674-60d142c64a5b" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesAddressTypeAxis_d1b8554d-a1b0-44cd-aa75-7e6c73e3f744" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_EntityAddressesAddressTypeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_dei_EntityAddressesTable_4f7d0307-09d4-4427-b674-60d142c64a5b" xlink:to="loc_dei_EntityAddressesAddressTypeAxis_d1b8554d-a1b0-44cd-aa75-7e6c73e3f744" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_d1b8554d-a1b0-44cd-aa75-7e6c73e3f744_default" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_AddressTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_dei_EntityAddressesAddressTypeAxis_d1b8554d-a1b0-44cd-aa75-7e6c73e3f744" xlink:to="loc_dei_AddressTypeDomain_d1b8554d-a1b0-44cd-aa75-7e6c73e3f744_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_07f0f5ff-271d-47f3-b186-c5036d37b6ba" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_AddressTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_dei_EntityAddressesAddressTypeAxis_d1b8554d-a1b0-44cd-aa75-7e6c73e3f744" xlink:to="loc_dei_AddressTypeDomain_07f0f5ff-271d-47f3-b186-c5036d37b6ba" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_OtherAddressMember_138f7a92-93a9-4042-a4b8-29a96a7fa73c" xlink:href="https://xbrl.sec.gov/dei/2021/dei-2021.xsd#dei_OtherAddressMember"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_AddressTypeDomain_07f0f5ff-271d-47f3-b186-c5036d37b6ba" xlink:to="loc_dei_OtherAddressMember_138f7a92-93a9-4042-a4b8-29a96a7fa73c" xlink:type="arc" order="0"/>
  </link:definitionLink>
</link:linkbase>
