A man works at a New York newspaper as an advice columnist to despairing readers, writing under the name "Miss Lonelyhearts." His editor is a cynical older man named Shrike who mockingly compares Miss Lonelyhearts to Jesus Christ. Miss Lonelyhearts decides he no longer finds the thirty letters he receives each day amusing. He reads through three letters that speak of unendurable emotional pain. Miss Lonelyhearts thinks that Christ is the answer, but he knows that Shrike would mock him if he discussed Christ. Shrike says that art is the answer, as art is distilled from suffering.
Miss Lonelyhearts has a few drinks at a speakeasy, where Shrike tells him to stop brooding and instead embrace more indulgent values. Miss Lonelyhearts returns home to his one-room apartment, where he has nailed a figure of Christ to the wall. Miss Lonelyhearts dreams about a time in college when he and two friends bought a young lamb to roast. Miss Lonelyhearts wants to sacrifice the lamb to God first. In a meadow, he chants "Christ" and tries to kill the lamb, but his knife blows are inaccurate, and the wounded lamb escapes. Later, Miss Lonelyhearts pleads with his friends to put the lamb out of its misery, but they stay put. He finds the lamb himself, crushes its head with a stone, and leaves its carcass to the flies.
Miss Lonelyhearts has an obsession with keeping inanimate objects in order. He thinks of Betty, who always provided order. Confused and irritated when he goes to Betty's apartment, his tongue turns into a "fat thumb" and he has difficulty speaking. He thinks about how Betty had accepted his marriage proposition two months earlier, and how he had guiltlessly avoided her thereafter. Miss Lonelyhearts says he has a Christ complex and loves humanity. Betty says she loves him, and he admits he loves her. She tells him to leave her alone, as he has made her feel bad.
Miss Lonelyhearts goes to the speakeasy and meets some friends. They complain about female writers and tell stories of literary women who are put in their place by rape. Miss Lonelyhearts thinks his friends have lost their way, but they criticize his approach to religion as too literary and personal. Miss Lonelyhearts collides with a man, accidentally spilling his drink, and gets punched in the mouth.
Later, Miss Lonelyhearts and his friend Ned Gates leave the speakeasy and head through the snow to the park. They drag an old man from a toilet, ridiculing and interrogating him as Miss Lonelyhearts pretends to be a psychologist. The old man cries and Miss Lonelyhearts twists his arm, feeling like he is twisting the arms of all his readers. Miss Lonelyhearts gets hit from behind with a chair.
Hung over, Miss Lonelyhearts wakes up and tries various methods to warm his heart—hot water, whisky, coffee, and exercise—before thinking of sex. His only option for such release besides Betty is Mary Shrike. Mary will kiss him because she hates Shrike, but will not sleep with him. Miss Lonelyhearts goes to Mary's place, where he is not surprised to find Shrike at the door. The men bicker about Mary, and Shrike says his wife has selfishly fought to remain a virgin and claims that he raped her. Mary comes into the room and tells Miss Lonelyhearts to join her in the bedroom. He does, and Shrike leaves the apartment. Miss Lonelyhearts and Mary go to a Spanish restaurant, but the dreamy atmosphere depresses him. He asks Mary to sleep with him, but she refuses. At the door to her apartment, they kiss, but she is afraid Shrike will hear them. She says if Shrike is not inside she will let him in. Miss Lonelyhearts hides as Shrike comes to the door.
At work, Miss Lonelyhearts receives a letter from a woman named Fay Doyle who says she is unhappily married to a "cripple." She has seen Miss Lonelyhearts in the speakeasy, wants his advice about her married life, and has included her phone number in the letter. Miss Lonelyhearts calls Mrs. Doyle from a phone booth and meets her in the park. He takes the large, brutish woman to his apartment, where they have sex. She tells him about her older, crippled husband, and says that her daughter, Lucy, is not his. Fay recounts the story of how she came to marry her husband, of her unhappiness with him, and of her regret. Miss Lonelyhearts assures her that her husband must love both her and Lucy.
After Mrs. Doyle leaves, Miss Lonelyhearts gets sick. He falls asleep but then wakes up as Betty enters his room with nourishment. He apologizes for his actions the other day, and she blames his job and tells him to quit. Miss Lonelyhearts says that quitting would make no difference, and explains how his job has made him suffer. He sees that Betty does not understand him. She speaks of the benefits of country living until Shrike comes in, at which time she leaves. Shrike describes various lifestyle choices that might potentially satisfy Miss Lonelyhearts, but rejects all of them as impossible on various grounds. Shrike mockingly maintains that only a life of God and worship can provide hope.
Betty continues visiting Miss Lonelyhearts. When spring comes she takes him to her aunt's farm in Connecticut. They install themselves in the musty farm, cleaning house, cooking dinner, and going down to the lake. Miss Lonelyhearts tries to seduce Betty, but stops when she says she is a virgin. He meets an anti-Semitic gas station attendant and finds the forest's undergrowth depressing. When Betty hangs up wet clothes in the nude, Miss Lonelyhearts kisses her and they tumble into the grass.
Miss Lonelyhearts and Betty return to New York a few days later. He knows he is not cured, as he has not been able to forget his readers' letters. He watches the crowds in the streets, thinking of how their dreams have been made "puerile" by the media. Miss Lonelyhearts realizes that he, too, dreams—about Christ—but fails at it because of lack of humility. He vows to be humble.
In his office, Miss Lonelyhearts reads a letter from a woman who calls herself "Broad Shoulders" and tells a long story about debt and her abusive husband. At the speakeasy, a man named Peter Doyle, whose foot is crippled, introduces himself to Miss Lonelyhearts. He says that Mrs. Doyle told him he should invite Miss Lonelyhearts to dinner if he ran into him. Miss Lonelyhearts accepts. Later, Doyle hands Miss Lonelyhearts a letter he has written to him. In the letter Doyle tells Miss Lonelyhearts about his disability and his job and repeatedly asks what the point of it all is. After Miss Lonelyhearts finishes it, he accidentally touches Doyle's hand under the table, quickly retracts his own hand embarrassedly, but then clasps Doyle's hand firmly.
Miss Lonelyhearts and Doyle leave the speakeasy, drunk, and go to Doyle's house. Doyle curses his wife, who flirts with Miss Lonelyhearts. When Doyle protests, Fay hits him with a newspaper. The two men hold hands again, prompting Fay to call them "fairies." Miss Lonelyhearts urges Fay to promote her husband's strength, but he knows that his reluctance to speak about God reduces his advice to the meaningless level of his columns. Doyle tells his wife he loves her, and she grudgingly forgives him and sends him out for liquor. After he leaves, Fay resumes trying to seduce Miss Lonelyhearts. When she gets more forceful, he hits her repeatedly and then leaves.
Miss Lonelyhearts spends three days in bed. Shrike and four others come to his door. Shrike says they want to play a game involving Miss Lonelyhearts's letters. They take a cab to a party at Shrike's apartment. Betty is there as well. Shrike introduces Miss Lonelyhearts to the guests as a moral and spiritual crusader. He directs each of the guests to answer one letter addressed to Miss Lonelyhearts, and says that Miss Lonelyhearts will analyze their responses and provide guidance.
Shrike hands out the letters, synopsizing them first. He hands Miss Lonelyhearts one letter, but Miss Lonelyhearts drops it without reading it. Betty leaves, and Miss Lonelyhearts follows her. Shrike reads the letter he gave Miss Lonelyhearts, which is from Peter Doyle, and denounces Miss Lonelyhearts for allegedly attempting to rape Fay. Shrike says his faith in "the master" is unshaken, however.
Miss Lonelyhearts catches Betty, who is wearing a light blue party dress, outside Shrike's apartment. She reluctantly accepts his invitation to a soda. He lies and tells her he has quit his job and will try to get an advertising job. After they flirt and laugh, Betty cries, though what Miss Lonelyhearts calls the "rock" in him is unmoved. She reveals that she is pregnant. Though she wants an abortion, Miss Lonelyhearts convinces her to marry him. They make plans about their life together as he returns her home. He remains unfeeling.
Miss Lonelyhearts gladly accepts a fever that comes after a long night. He shouts out Christ's name. He identifies his heart and mind with God. He plans his life and job anew and offers drafts of his column to God, who approves of everything. Miss Lonelyhearts answers the doorbell and sees Doyle walking up the stairs. He thinks of it as a chance to embrace and heal the cripple, and runs down to greet him. Doyle carries something inside a newspaper, and reaches inside when he sees Miss Lonelyhearts. Doyle tries to flee, but Miss Lonelyhearts catches him. Betty enters the apartment, starts up the stairs, and tells them to stop. Doyle panics and tries to get rid of his package, taking his hand out. The gun inside explodes and Miss Lonelyhearts falls, rolling with Doyle down the stairs.