A Southern Gothic novel, the Heart is a Lonely Hunter focuses on four characters who confide in one man, John Singer, a deaf-mute. The characters include Mick, a teenage girl whose parents own the boarding house where Singer lives, Biff, the owner of the local cafe, Jake Blount, a union organizer, and Dr. Copeland, a black man who wants to build up his community. The novel explores the deep isolation felt by all of the characters, including Singer himself, who has been left alone by his sick friend.
The book begins with a focus on the relationship between two close friends, John Singer and Spiros Antonapoulous. The two are described as deaf-mutes who have lived together for several years. Antonapoulous becomes mentally ill, misbehaves, and despite attempts at intervention from Singer, is eventually put into an insane asylum away from town. Now alone, Singer moves into a new room.
The remainder of the narrative centers on the struggles of four of John Singer's acquaintances: Mick Kelly, a tomboyish girl who loves music and dreams of buying a piano; Jake Blount, an alcoholic labor agitator; Biff Brannon, the observant owner of a diner; and Dr. Benedict Mady Copeland, an idealistic black physician.