The first chapter of The Heart Is a Lonely Hunter introduces us to John Singer and Spiros Antonapoulos, two good friends who live together in a town in the Deep South and who are both deaf-mutes. Antonapoulos works in his cousin's fruit store, and Singer works as a silver engraver in a jewelry shop. They spend ten years living together in this way.
One day Antonapoulos gets sick, and even after he recovers he is a changed man. He begins stealing and urinating on buildings, and exhibiting other erratic behavior. Finally, Antonapoulos's cousin sends him to a mental asylum, although Singer would rather have Antonapoulos stay with him. After Antonapoulos leaves, Singer moves into a local boarding house in town run by a family named the Kellys.
The narrator then introduces us to Biff Brannon, the proprietor of the New York Café, the establishment in town where Singer now eats all his meals. Biff is lounging on the counter watching a new patron named Jake Blount, as the constantly drunk Jake is intriguing. Blount goes over and sits with Singer and begins talking to him as though the two are good friends. Then Singer leaves. Once Jake realizes in his drunken stupor that Singer has left, he goes into an alley and begins beating his head and fists against a brick wall until he is bruised and bloody. The police bring Jake back to the café, and Singer volunteers to let the drunk stay the night with him.
The narrative shifts to the perspective of Mick Kelly, the young teenage daughter of the couple who own the boarding house where Singer is staying. Mick spends her summer days looking after her two younger brothers, Bubber and Ralph. Mick is passionate about music, and she tries to make a violin out of a ukulele and strings from various different instruments. She is frustrated when her attempt fails.
The narrative switches to Blount's point of view. Jake applies for and lands a job as a mechanic at a local carnival. He tries to tell some workers about his socialist ideas on his way home, but they laugh at him. He soothes himself by going back to John Singer's place, talking to him and drinking.
Then the narrative switches to Dr. Copeland's perspective. Dr. Copeland is a black physician in town. He is angered by a story his daughter, Portia, tells him about a scam artist who took lots of black people's money. He wishes that his children had grown up to be well-educated, successful leaders for the black race rather than accepting the traditional, demeaning, menial jobs that are usually available to blacks in the South at this time. Dr. Copeland remembers a night when John Singer lit a cigarette for him—the first time the Doctor has experienced an act of courtesy from a white man in his entire life.
By the end of Part One, Mick, Biff, Jake, and Dr. Copeland have all begun to visit Singer regularly, all taking comfort in him as a confidant.
At the opening of Part Two, Mick throws a party with kids from school. During the party, she and her neighbor Harry Minowitz take a stroll around the block. Harry, a Jewish boy, tells Mick how much he hates the Nazis. Later that night, Mick, hiding in the bushes outside a house in the rich neighborhood, overhears on the radio a Beethoven symphony for the first time. She is very moved by it.
Biff's wife, Alice, dies after surgery to remove a tumor. Biff is not overly sad about it because he and Alice had fallen out of love. He and his sister-in- law, Lucile Wilson, and Lucile's daughter. Baby, come over to talk to Biff before they go to the funeral. Biff tells Lucile that once he beat up her ex-husband, Leroy, because Leroy had been bragging about how he beat her. The three of them then set off for the funeral.
Dr. Copeland's youngest son, Willie, is convicted of attempted manslaughter after getting in a fight at a strip club. Willie and is sent to prison. Dr. Copeland starts to feel ill, and soon discovers that he has tuberculosis of the lungs. A few days later, Portia invites Dr. Copeland to come to a family reunion at her house, as his estranged older sons Buddy and Hamilton, as well as Grandpapa (his father-in-law) are going to be in town.
Jake Blount tells Singer about his socialist beliefs and about the books by Marx and Veblen he has read. Blount tells Singer how badly he wants to tell all workers about the evils of capitalism, as he wants to stage a revolution that will result in a more equitable division of labor and profit. On his way home, Jake sees a quote from the Bible written on a wall. He writes underneath the quote that he wants to meet the man who wrote it, but the man never shows up.
One day, when Mick is sitting out on the front steps with her brother Bubber, Bubber accidentally shoots Baby Wilson in the head with his friend's BB gun. Baby has to be rushed to the hospital, and the six-year-old Bubber feels so bad about the event that he tries to run away from home. Mick and her family find Bubber wandering along the road, trying to hitch a ride to Atlanta.
Dr. Copeland throws his customary Christmas party at his house. Once the guests are assembled, he delivers a powerful speech about the importance of education for black people. He also tells the guests about Karl Marx, whom he believes was a great writer and thinker. Dr. Copeland feels happy knowing that he is helping his people toward achieving justice, though he later worries that his guests will not remember his words for long.
Singer misses Antonapoulos terribly, and he writes his friend a letter telling him about the four visitors who come to see him all the time. Then Singer takes a few days off from work and goes to the mental hospital to see Antonapoulos, who is now sick with nephritis. Singer gives his friend a moving picture machine for Christmas.
Biff Brannon redecorates his bedroom after Alice's death, and one day he finds some old perfume of hers and begins wearing it. Lucile and Baby come to eat at the café; Baby is still bald from her surgery and more ill-tempered than she was before her accident. Biff realizes that he wishes Mick and Baby could be his own children.
Mick begins to write music in her spare time. Songs come into her head and she writs them down in a notebook she hides beneath her bed in a hatbox. She and Harry Minowitz make plans to kill Hitler. One day during a wrestling match Mick and Harry suddenly feel attracted to one another, but nothing happens.
Dr. Copeland and Portia have note heard from Willie in six weeks. Finally Portia receives word that Willie was punished because one of his friends was rude to a prison guard. Willie was tied up and locked in a cold room for three days; when he was let out, his feet were gangrenous and had to be cut off. Dr. Copeland goes to the courthouse to talk to a white judge that he knows, but a racist sheriff picks a fight with the Doctor, beats him, and throws him in jail.
Mick and Harry Minowitz decide to take a bike trip to a lake to go swimming because the weather has gotten so hot. They end up having sex, and Harry is very upset about it; he is afraid his mother will be able to tell what has happened. Harry tells Mick that he is going to leave town, but that he will write to her once he has found work to make sure she is doing alright.
Jake Blount meets the man who wrote the quote from the Bible on the brick wall; the man's name is Simms, and he preaches on the sidewalks. Simms starts coming to preach at the carnival where Jake works, and Jake occasionally makes fun of him. One day, Jake goes to see Singer, who is just returning from seeing Dr. Copeland. Singer tells Blount the news about Willie's feet. Jake says he would like to try to help Willie, so he and Singer go to Portia's house, where Willie is staying. Jake gets drunker and drunker during the visit, and neither Portia nor Willie wants Jake to get involved in Willie's incident because they think it will just lead to more trouble. Jake accidentally stumbles into the room where Dr. Copeland is lying in bed recovering, and the two men get into a heated debate about Marxism and the best way to take action to change society. Despite their seemingly similar ideologies, the two men get in an argument and Blount storms out.
Mick takes a job at Woolworth's to help support her family, but then wonders if she has made a bad choice, realizing she will likely have to drop out of high school. Mick visits Singer and asks him if he thinks it a good idea to take the job. When he nods in assent, Mick feels reassured.
Singer then sets off to see Antonapoulos once again. He brings many wrapped gifts with him along with a fruit basket and a basket of strawberries. However, when Singer arrives, the orderly tells him that Antonapoulos has died. The shocked Singer wanders about listlessly, returns home on the train, goes to work the next day, and shoots himself in the chest when he gets back to his room in the evening.
In Part Three of the novel, we briefly see snapshots of the four main characters on a day not long after Singer's death. Dr. Copeland is sent to live on Grandpapa's farm—a move the Doctor does not want to make but about which he has no choice, as he is too sick to take care of himself anymore. Dr. Copeland feels that his life purpose—striving to attain justice for the black people—is an unfinished failure.
Jake Blount is angry that Singer has died, as he himself has spent much of the last year confiding in a man who is now dead. Blount tries to find Dr. Copeland to make amends with him after their previous argument, but Portia tells Blount that Dr. Copeland has already left for Grandpapa's. Jake decides to take the next train out of town to try and start anew somewhere else.
Mick Kelly has decided to continue working at Woolworth's. She does not understand why Singer killed himself, but she tries not to let it bother her too much anymore. She reflects that lately she has not had any time or energy to write music, but she nonetheless resolves to start saving for a little piano. Even though nobody forced Mick to take the job at Woolworth's, she feels cheated. However, she still maintains optimism and resolves to pursue her plans.
Biff Brannon keeps on working at the New York Café, pondering the patrons as he always has. At the café late that night, Biff thinks that Singer's death is a riddle that will remain a mystery for a long time. Biff experiences a brief epiphany about the meaning of life, and then prepares himself to greet the approaching day.