Larry Donner, a frustrated novelist, battles a crippling case of writer's block, exacerbated by his bitterness towards his ex-wife, Margaret, who has found fame off the success of his manuscript while he struggles financially. Seeking a creative spark, Larry decides to teach at a community college, where he meets a timid middle-aged student named Owen Lift, who is ensnared in the oppressive grip of his overprotective mother.
Owen's mother is a formidable presence, riddled with paranoia at the thought of being sent to a retirement home. This dread leads Owen to entertain dark fantasies of eliminating her, though he lacks the resolve to act on them. When Larry encourages his students to delve into film for a deeper understanding of narrative, Owen becomes captivated by Alfred Hitchcock's Strangers on a Train—a story where two strangers plot to murder on behalf of each other, believing it to be the ideal way to circumvent suspicion.
One day, as Larry publicly bemoans his ex-wife’s success, a sinister idea begins to flicker in Owen's mind. He hatches a plan to ensure Larry pays him back for his mother’s murder by stalking Margaret to Hawaii, where she is hosting a cruise ship book signing. Owen's intent is to push her overboard, thus triggering a strange and dangerous interplay between them.
Back in California, Owen shares with Larry the news of Margaret's supposed demise and suggests that he now has a "debt" to repay—one that requires him to commit matricide, or Owen will expose Larry as the orchestrator of Margaret's disappearance. Alone on the beach, consumed with guilt over Margaret's fate, Larry becomes increasingly paranoid, particularly as a news report surfaces about the investigation into his ex-wife's disappearance. In a bid to escape scrutiny, he seeks refuge with Owen and Mrs. Lift, soon realizing just how overwhelming she can be.
Despite the oppressive atmosphere, Larry initially resists the urge to act against her. Yet, when Mrs. Lift pushes Owen too far, Larry reluctantly agrees to eliminate her, giving in to the dark impulses stirred up by his artistic frustrations. As pressure mounts, Larry bolts from the Lift household, making a desperate escape to Mexico with Owen and his mother, attempting to evade the encroaching doom.
Their chaotic travel ignites further tension, culminating in a confrontation between Larry and Mrs. Lift aboard the train. In a moment of unexpected camaraderie, both Larry and Owen work together to save her, although Mrs. Lift's gratitude is directed solely at Owen, leaving Larry to grapple with his feelings of inadequacy.
Recovering in a hospital, Larry discovers that Margaret is alive and intends to profit off her experience by selling it to the highest bidder. This news liberates Larry from his fixation on her, inspiring him to focus on his own writing, leading to the creation of his novel, Throw Momma from the Train, which narrates his tumultuous relationship with Owen and Mrs. Lift.
As time passes, Owen visits Larry with news of his mother’s natural death, accompanied by the surprising revelation that he too has penned a book—a children’s pop-up narrative drawing from their shared experiences, albeit in a sanitized version. Larry's initial outrage over this perceived literary theft is quelled when he learns of the book's light-hearted nature, prompting a moment of reflection and growth in their relationship.
Eventually, after both have tasted success in their literary careers, Larry, Owen, and Larry's girlfriend Beth embark on a much-deserved vacation to Hawaii, celebrating how far they've come while recalling the poignant lessons documented in Larry's bestselling work. Their bond has transformed from rivalry to genuine friendship, unearthing a profound companionship formed through adversity.
