In a New York City office, Miss Lonelyhearts struggles to meet his upcoming deadline. The writer behind a newspaper advice column, Miss Lonelyhearts is bogged down by the problems that New Yorkers write to him about—though he first began this job knowing that he and his colleagues didn’t take the column seriously. His boss Shrike offers a satirical suggestion, telling Miss Lonelyhearts that he should suggest to readers that art will cure their problems. Miss Lonelyhearts wants to suggest Christianity as a potential balm to readers’ worries, but he knows that Shrike doesn’t agree with his religious beliefs.
Outside of the office, Miss Lonelyhearts tries to escape work. However, he finds that he can’t stop thinking about all the readers who write to him, desperately asking for help and advice. While trying to unwind with a few drinks at a speakeasy, Miss Lonelyhearts runs into Shrike, who pretends that he’s about to hit a woman, Miss Farkis, as a joke.
Unable to calm himself down and growing more irritable, Miss Lonelyhearts suddenly recalls Betty, the woman to whom he recently proposed and with whom he began to plan his life. The two, however, haven’t spoken since the proposal two months ago. Miss Lonelyhearts decides to visit Betty, but he doesn’t seem to genuinely care for her. He has to force himself to kiss her, and although the couple verbally expresses their love for one another, Betty breaks into tears and says that she’s only happy when Miss Lonelyhearts isn’t around.
Perhaps realizing that his relationship with Betty is far from ideal, Miss Lonelyhearts decides to call up a different woman the next day, wanting to see if sex will make him feel better. The woman he decides to call is Mary, Shrike’s wife. Together, Miss Lonelyhearts and Mary head to El Gaucho, where Mary wants to dance. She refuses when Miss Lonelyhearts repeatedly asks her to sleep with him, telling him instead about her past and her mother’s death. When they leave El Gaucho, Miss Lonelyhearts ignores Mary’s refusal and starts to take off her clothes.
The next woman Miss Lonelyhearts meets up with is Mrs. Doyle, who sends him a letter asking if they can meet in person to discuss her failing marriage. He invites Mrs. Doyle to his apartment, where they have sex. Afterward, Mrs. Doyle starts to tell Miss Lonelyhearts about her unfulfilling marriage to Mr. Doyle, a disabled man she used to spend time with out of pity. Following this interaction, Miss Lonelyhearts falls sick and sequesters himself in bed for three days. Shrike and Betty try to cheer Miss Lonelyhearts up, but to no avail: Miss Lonelyhearts can’t stop thinking about readers’ letters.
One day, at the speakeasy, Miss Lonelyhearts meets Mr. Doyle. At first, Miss Lonelyhearts can’t understand a word that Mr. Doyle is saying, and he realizes that Mr. Doyle isn’t trying to be understood, which excites him. Mr. Doyle pulls out a letter, in which he details his physical and mental struggles as a disabled man, and Miss Lonelyhearts holds Mr. Doyle’s hand beneath the table in support.
Miss Lonelyhearts has dinner at the Doyles’ home, during which Mrs. Doyle overtly flirts with him. The Doyles get into an argument because of this, and Miss Lonelyhearts allows himself to share a religious message, proclaiming that “Christ is love”—and that Mrs. Doyle should allow her husband to “conquer” her in bed. Mr. Doyle then leaves to buy gin from the store. With her husband gone, Mrs. Doyle tries to get Miss Lonelyhearts to have sex with her. He lashes out, hitting her again and again before escaping.
Miss Lonelyhearts stays in bed for another three days and ultimately comes down with a fever that triggers a religious awakening: he believes that he’s transformed into God. Following this awakening, his doorbell rings. He glimpses Mr. Doyle at the door and rushes to embrace him, seemingly wanting to offer love and kindness in his awakened form. However, Mr. Doyle is carrying a gun wrapped in newspaper, determined to avenge his wife. The two men get into a tussle that ends in Mr. Doyle’s gun exploding, shooting Miss Lonelyhearts as they fall down the staircase together.