Misanthropic New York best-selling romance novelist Melvin Udall has a struggle with obsessive-compulsive disorder (OCD), which manifests in his numerous peculiar habits. He insists on using a bar of soap only once before discarding it, utilizes paper towels to handle public restroom fixtures, dodges sidewalk cracks, adheres to strict rituals involving switches and locks, and maintains consistent routines. His breakfasts are always consumed at the same table in his favorite diner, where he arrives with his own plastic cutlery. The only server who can bear his odd and abrasive demeanor is Carol Connelly.
Melvin's neighbor, Simon Bishop, a gay artist, unexpectedly brings a new model, Vincent Lopiano, into his life. Vincent seizes this opportunity to scout Simon's apartment, eventually facilitating a break-in where Simon is brutally attacked, leaving him nearly dead. Following this, Simon's agent, Frank Sachs, coerces Melvin into caring for Simon's beloved pet, a Griffon Bruxellois named Verdell, during Simon's hospital stay. Initially reluctant and disinterested in the responsibility, Melvin slowly forms a bond with Verdell, which keeps him connected to Simon once he recovers.
As Melvin becomes accustomed to his new routine, he faces disruption when Carol decides to relocate closer to her home in Brooklyn to better support her asthmatic son, Spencer. Struggling to adapt to the absence of his preferred waitress, Melvin offers to cover Spencer's substantial medical costs if Carol returns to the diner, a gesture that leaves her grateful yet wary. Carol expresses her disbelief in Melvin’s intentions, firmly declaring that there will be no romantic involvement. In a moment of embarrassment, Melvin insists that it is she who has made the situation personal.
Meanwhile, Simon grapples with crippling medical debts that lead him to bankruptcy and despair. Encouraged by Frank, he reluctantly agrees to visit his estranged parents in Baltimore to seek financial assistance. Reluctantly drawn into the situation, Melvin consents to drive Simon there, utilizing Frank’s Saab 900 convertible for the journey. To shield himself from the uncomfortable idea of Simon potentially pursuing him, Melvin uninvitingly invites Carol, reminding her of her debt to him, which she reluctantly accepts. As their road trip progresses, the three characters share deeper conversations; Simon unveils the pain of his estrangement due to his sexuality, while Carol relates to him, and Melvin’s biting comments gradually soften.
Once they reach Baltimore, Carol persuades Melvin to join her for dinner. What starts as flattery soon spirals into discomfort when Carol confronts Melvin about his true feelings for her. In his awkwardness, Melvin deflects her advances, suggesting, in jest, that perhaps Simon needs to explore sexual relations to "cure" his homosexuality. Carol, hurt by this thought, seeks solace in Simon’s company, leading to an emotional reconnection that rekindles Simon’s passion for his art. He sketches Carol, capturing her femininity in a way that allows her to feel cherished beyond the usual romantic entanglements. With newfound confidence, Simon reaches out to his mother without seeking financial help, affirming he is capable of thriving on his own.
Upon returning to New York, Carol informs Melvin that his derogatory demeanor has pushed her away, and she no longer wishes to associate with him. Meanwhile, Simon, now without a home, is offered a place to stay in Melvin’s spare room. Recognizing the weight of Melvin's act of kindness as evidence of personal growth, Carol experiences a change of heart and reaches out to apologize. Though their relationship remains intricate and somewhat strained, Simon eventually encourages Melvin to confess his feelings for Carol. Melvin visits Carol, who shows a tentative willingness to explore a relationship with him, reassured by her mother's wisdom that no connection is free from imperfections. The film concludes with Melvin and Carol walking together; as he opens the door for her at a morning pastry shop, he unwittingly steps on a crack in the pavement but seems unbothered by it.
