- The main character of the novel. Miss Lonelyhearts works as an advice columnist to his miserable readership at a New York newspaper, under the eye of his editor, Shrike. Miss Lonelyhearts is profoundly depressed by the letters he receives and by the moral climate around him. He believes that Jesus Christ is the only answer, but he has difficult integrating the concepts of Christian love into his personal life, as in his failed relationship with Betty and his affairs with Mary Shrike and Fay Doyle.
in-depth analysis of Miss Lonelyhearts.
- Miss Lonelyhearts's editor at the newspaper. Cynical, hedonistic, grandiloquent, and a womanizer, Shrike is the novel's anti-Christ of sorts. He is married to Mary, who he claims beats him and refuses to give up her virginity. Still, Shrike lets Mary go out with other men to save money. He mocks Miss Lonelyhearts most when it comes to religion, ridiculing his identification with Jesus and forcing him to dispense false hopes to his readership.
in-depth analysis of Shrike.
- A woman to whom Miss Lonelyhearts had proposed marriage two months prior to the events of the novel, but whom he now avoids her until desire for sex makes him visit her again. Betty is ordered, earnest, and virginal, and attributes Miss Lonelyhearts's illness to city life—she prizes her aunt's old farm above anything else. Betty's naïveté also disallows her from completely understanding Miss Lonelyhearts's plight and makes her an easy target for his verbal abuse.
in-depth analysis of Betty.
- A large, nearly grotesquely voluptuous and brutish woman. A great beauty when she was younger, Fay married the disabled Peter Doyle when she did not have enough money to support her daughter by another man. She is unhappy with her life and especially with Doyle, whom she verbally and physically abuses. Fay takes her frustrations out with aggressive advances on Miss Lonelyhearts, who plays the traditionally feminine role of resister to her pursuit.
- A worker for a gas company whose foot has been crippled from birth. Peter, who was married by convenience to the much stronger Fay, wonders what the point of life is and why he keeps on struggling. He is also angry and threatened that Fay's daughter Lucy is his biological child. Peter plays a submissive role to Fay while trying to overlook her sexual advances on other men, notably Miss Lonelyhearts.
in-depth analysis of Peter Doyle.
- Shrike's wife. Mary has been having an ongoing affair with Miss Lonelyhearts and other men for some time, but Shrike allows her this, as it saves him money. Still, Mary only goes so far as to kiss the men. She enjoys the dreamy atmospheres of nightclubs and restaurants and clearly wishes to escape from her dreary home life.
- An anonymous person who pens the longest letter Miss Lonelyhearts receives during the novel. "Broad Shoulders," like Miss Lonelyhearts's other readers, writes poorly, in a wrenching torrent of run-on sentences and misspellings that details her life of suffering. She says that she calls herself "Broad Shoulders" because that is how she feels about life and herself.
- An old man Miss Lonelyhearts and his friend Ned Gates find in a toilet in the park one night. His real name George B. Simpson, the old man is interrogated mercilessly and mockingly by the two men.
- An irritable friend of Miss Lonelyhearts's who takes delight in verbally torturing the old man. Ned does, however, try to get Miss Lonelyhearts to lay off the old man after a while.
- A young woman with whom Shrike has a date at the speakeasy. Miss Farkis is interested in intellectual discussions, and is seduced by Shrike's eloquent speeches.
Gas station attendant
- A worker at a gas station near Betty's farm. The attendant openly reveals his anti-Semitic beliefs when Miss Lonelyhearts talks to him while gassing up the car.
- A co-worker at the newspaper who fills in for Miss Lonelyhearts the day he is too hung over to go to work.