Doxorubicin(DOX)isapowerfulantitumoragentwithawell-knowncardiaotoxicsideeffects.Inthecurrentstudy,theameliorativecombinedimpactsofmontelukast(Mont)andKlothoagainstdoxorubicin-inducedcardiactoxicitywereexamined.Fifty-sixadultmalerats(2monthsageandweighting150–200g)weregroupedinto7groups(8ratspergroup).AnimalsreceiveddoxorubicinaloneorincombinationwitheitherMontorKlotho.After2weeksoftreatments,serumsampleswereexaminedtoassessthechangesincardiacactivitybiomarkerssuchasLDH,CK-MB,cardiactroponin-I(cTn-I),andheartfattyacidbindingprotein(H-FABP).SerumchangesofIL-6,induciblenitricoxidesynthase(iNOS),andcaspase-3levelswereassayed.Theoxidativestressbiomarkerssuchastotalantioxidantcapacity(TAC)andinflammatory(ratIL-1βandratTNF-α,)andanti-inflammatory(ratIL-10)cytokineswereexamined.Hearthistologyandtransforminggrowthfactor-β1(TGF-β1)immunoreactivityweremeasured.DOXinducedcardiomyopathy,whichwasreflectedbytheincreasesinallexaminedcardiacparameters.Real-timePCRconfirmedthatDOXupregulatedtheexpressionofTNF-αandIL-1βanddecreasedtheexpressionofIL-10.Moreover,DOXshowedmarkedelevationintheSTsegmentTwavecomplex,causingprofoundtachycardia.Hearthistologyassessmentsshowedcardiaccellnecrosis,inflammatorycellinfiltration,interstitialcongestion,andincreasedTGF-β1immunoreactivity.MontelukastandKlothoadministrationamelioratedallthealteredparameterswhenadministeredaloneorincombinationtoDOX-intoxicatedrats.Klothowasmoreeffectivecomparedwithmontelukastintermsofreductionsinheartrate,STsegmentTwavecomplexelevation,cardiacenzymes(lactatedehydrogenase;LDH,creatinekinase-MB;CK-MB,cardiactroponinI;cTn-I,heartfattyacidbindingprotein;H-FABP)cardiachistology,andcaspase-3levelsandincreasesinTACactivity.MontelukastwasmoreeffectiveinreducingserumlevelsofIL6andiNOS,expressionofTNF-αandIL-1β,andtheupregulationofIL-10expression.Theco-administrationofbothdrugsledtosignificantlymoresynergisticresultsintermsofreducingcardiactoxicity.Inconclusion,montelukastandKlothoeitheraloneorincombinationwereconfirmedtobeeffectiveinsuppressingDOX-inducedcardiactoxicityinrats.