In the story, Miss Lonelyhearts is the pseudonym for an unnamed male newspaper columnist writing an advice column for the lovelorn and lonesome, a duty that the other newspaper staff consider to be a joke. As Miss Lonelyhearts reads letters from desperate New Yorkers, he feels terribly burdened and falls into a cycle of depression, accompanied by heavy drinking and occasional bar fights. He is also the victim of the pranks and cynical advice of Shrike, his feature editor at the newspaper.
Miss Lonelyhearts tries several approaches to escape the terribly painful letters he has to read: religion, trips to the countryside with his fiancée Betty, and sexual affairs with Shrike's wife and Mrs. Doyle, a reader of his column. However, Miss Lonelyhearts's efforts do not seem to ameliorate his situation. After his sexual encounter with Mrs. Doyle, he meets her husband, a poor crippled man. The Doyles invite Miss Lonelyhearts to have dinner with them. When he arrives, Mrs. Doyle tries to seduce him again, but he responds by beating her. Mrs. Doyle tells her husband that Miss Lonelyhearts tried to rape her.
In the last scene, Mr. Doyle hides a gun inside a rolled newspaper and decides to take revenge on Miss Lonelyhearts. Lonelyhearts, who has just experienced a religious enlightenment after three days of sickness, runs toward Mr. Doyle to embrace him. The gun "explodes", and the two men roll down a flight of stairs together.
