A man works at the New York Post-Dispatch as an advice columnist to the despairing under the pen name "Miss Lonelyhearts." His editor, a cynical older man named Shrike, has printed out a mock-prayer comparing Miss Lonelyhearts to Jesus Christ. The prayer sits on Miss Lonelyhearts's desk. After beginning another reply that extols the virtue of faith, Miss Lonelyhearts decides he no longer finds the thirty letters he receives each day amusing. He reads through three more letters. The first is from a Catholic woman whose husband forces her to continue bearing him children despite the severe pain pregnancy causes her. The second is from a lonely sixteen-year-old girl, born without a nose and wondering if she should commit suicide. The third is from a boy who is unsure how to handle his younger deaf and dumb sister, who was recently raped.
Miss Lonelyhearts stops reading and thinks to himself that Christ is the answer, but he knows that if he discussed Christ he would get sick and Shrike would mock him. He reflects on his own ministerial New England "puritan" appearance. Shrike sidles up and dictates a reply to one of the letters. He says that art is the answer, as art is distilled from suffering. He dictates some more, then tells Miss Lonelyhearts to continue.
Miss Lonelyhearts leaves work to get a drink at a speakeasy. He walks through a park but, despite the temperate climate, sees no signs of spring in the arid ground. He contemplates asking his readers in tomorrow's column to water the ground with their tears. He thinks how Shrike will ridicule him at the speakeasy, telling him to give his readers "stones." Miss Lonelyhearts thinks he has already given his readers many stones, and has only one left, in his stomach. He wants to throw this stone, but finds no target.
After Miss Lonelyhearts has had three drinks at the half-empty speakeasy, Shrike shows up and says that Miss Lonelyhearts is brooding. Miss Lonelyhearts is unhappy to see him, but Shrike shrugs it off and tells him to "Forget the crucifixion, remember the Renaissance." Miss Lonelyhearts thinks how similar Shrike's expressionless face is to the "dead pan" trick used by comedians.
Shrike speaks highly of the indulgent, lascivious period of the Renaissance, which he says reminds him of a woman he is expecting. Miss Lonelyhearts is annoyed, and Shrike makes fun of him for loving only Jesus. Miss Farkis, Shrike's date, arrives, and Shrike berates her for her pretentious interest in discussing religion. Instead, he shows her a newspaper clipping about a pontiff who declared that prayers for a condemned murderer would be offered on an "adding machine."
The bartender asks the trio to move to the back room after Shrike makes a motion to hit the laughing Miss Farkis. In the back room, Shrike seduces Miss Farkis with his caresses until she pushes him away. While caressing her again, he makes a speech in which he jokingly compares himself to Jesus, and meditates upon the "wondrous jungle" underneath man's skin wherein lives a "bird called the soul." He criticizes the ways religion "hunts" the bird. Shrike ends his speech and buries his face into Miss Farkis's neck.