NovelistLarryDonner(BillyCrystal)struggleswithwriter'sblockduetohisresentmenttowardshisex-wifeMargaret(KateMulgrew),whostolehisbookandgarneredmainstreamsuccessandcriticalacclaimwithit.OwenLift(DannyDeVito)isatimid,middle-agedmanwhostillliveswithhisoverbearing,abusivemother(AnneRamsey).Owenfantasizesofkillinghismotherbutcan'tsummonthecouragetobringhisdesiresintofruition.AsastudentinLarry'scommunitycollegewritingclass,OwenisgivenadvicebyLarrytoviewanAlfredHitchcockfilmtogainsomeinsightintoplotdevelopment.HeseesStrangersonaTrain,inwhichtwostrangersconspiretocommitamurderforeachother,figuringtheirlackofconnectiontothevictimwill,intheory,establishaperfectalibi.HavingoverheardLarry'spublicrantthathewishhisex-wifedead,OwenformsaplantokillMargaret,believingthatLarrywillrespondbykillinghismother.
　　HetracksMargaretdowntoHawaiiandfollowsherontoacruiseship,apparentlypushingheroverboardwhileshetriestoretrieveanearringthatfellout.OwenreturnsfromHawaiitotellLarryofMargaret'sdeathandthatLarrynow"owes"himthemurderofhismother,lestheinformthepoliceLarrywasthekiller.AfterhavingspentthenightdrinkingaloneduringthehoursofMargaret'sdisappearance,Larrypanicsbecausehelacksasufficientalibi.That,alongwithanewsreportannouncingthepolicesuspectfoulplay,convincesLarryhe'stheprimesuspect.HedecidestostaywithOwenandhismotherinanattempttohidefromthepolice.LarrymeetsMrs.Lift,butdespiteherharshtreatmentofhimherefusestokillher.Eventually,whenMrs.LiftdrivesOwentothebreakingpoint,Larryfinallyrelentsandagreestogothroughwiththemurder.
　　Aftertwounsuccessfulattempts,LarryfleestheLifthomewhenMrs.Liftrecognizeshimasasuspectfromanewsbroadcastabouthisex-wife'sdisappearance.HeboardsatraintoMexicoand,surprisingly,OwenandMrs.Liftcomealongsoastoavoidhavingtolieforhim.Duringthejourney,Larry'spatiencewithMrs.Liftreachesitspinnaclewhensheimpolitelygiveshimadviceonwriting.Hefollowshertothecaboosewiththeintentofthrowingherfromthetrain,butstopsshortwhenshealmostfallsoffonherown.OwenbeginshavingsecondthoughtsabouthavinghismotherkilledandcomestohelpLarryrescueher.Mrs.Liftisgratefulathersonforsavingher,butunappreciativeofLarry'shelpandkickshim,resultinginhimlosinghisbalance,landingonthetracks,andbreakinghisleg.
　　Duringhisrecoveryinthehospital,LarrydiscoversMargaretisstillalive;shesimplyfelloverboardbyaccidentandwasrescuedbyaPolynesianfishermanwhomshehasdecidedtomarry.Muchtohisannoyance,LarrylearnsMargaretplanstoselltherightsofherordealfor$1.5milliondollars.Ontheadviceofafellowpatient,Larrychoosestofreehimselfofhisobsessionwithhisex-wifeandinsteadfocusonhisownlife,therebyfreeinghimofhiswriter'sblock.
　　Ayearlater,LarryhasfinishedanovelbasedonhisexperienceswithOwenandMrs.LiftentitledThrowMommafromtheTrain.Owenvisitsandinformshimthathismotherhasdied(ofnaturalcauses)andthathe'sgoingtoNewYorkCityforthereleaseofhisownbook.Unfortunately,Owenrevealshisbookisalsoabouttheirexperiencestogether.Thinkinghisbookhasbeenscooped,anenragedLarryproceedstostranglehim,butstopswhenOwenshowshimthebookisachildren'spop-upbookcalled,Momma,Owen,andOwen'sFriendLarrywiththestorydrasticallyalteredtobesuitableforchildren.Monthslater,Larry,Owen,andLarry'sgirlfriendBeth(KimGreist)vacationtogetherinHawaii,reflectingonthefinalchapterofLarry'sbook.LarryandOwen'sbookshavenowbecomebest-sellers,makingthembothsuccessfulwritersaswellasclosefriends.