The Neon Bible by John Kennedy Toole is a coming of age story about a young man living in a small rural town, who tries to remain sane while dealing with family strife and social awkwardness.

David is raised as an only child, living with his mother, father and his eccentric Aunt Mae. The family resides in town until his father loses his job and they have to relocate to the hills. This move drastically changes their way of life and limits David's ability to socialize with other children. David has no real friends except Aunt Mae. She is a singer who is eccentric and dresses flamboyantly. The entire town talks about her behind her back but she doesn't mind. Any attention is good attention to Aunt Mae.

Father gets a part-time job at a gas station and decides to fill the rest of his time planting crops behind the house. He uses one week's salary to buy seeds and tools. Mother is outraged because it leaves her no money to buy food. During a heated argument, Father hits her and almost does not return to the house. Shortly after this incident, Father is drafted to Italy to fight in the war. It provides relief for the family, because it puts an end to the domestic fighting, but they are all sad to say goodbye.

Aunt Mae starts working at the town war plant and plays a key role in its functioning. A revival comes to town, bringing Bobbie Lee Taylor from Tennessee. The town has not had a revival in a long time and it is much needed by the women missing their loved ones overseas. The war plant has a party and Aunt Mae ends up singing for the crowd. After that night she starts singing all around town with the band. She is never home anymore and Mother spends all day sitting in the crops or reading the letters Father sends from Italy. David is in sixth grade when they receive a telegram stating that Father died and was buried in Italy. They get a picture of white crosses, one of which is presumed to be his.

Mother goes a little crazy and can no longer function in public. Aunt Mae goes out with a much older man from the band named Clyde. David graduates grade school and starts working at the local drugstore. David meets Jo Lynne at the store. She is visiting her sick grandfather and fills his prescriptions. David takes her out one night and they kiss. Soon after that night Jo Lynne leaves town again, prompting David to suggest they marry. She slaps him and leaves the store. Aunt Mae is asked by Clyde to go to Nashville to try and make it in the music industry. She leaves David with Mother and promises to send for them. David returns to the house to find Mother in the hallway bleeding from the mouth. She dies that night. The preacher comes by the house the next day, just as David finishes digging a grave. He tries to take Mother to the state institution, not knowing she is dead. David shoots the preacher in the back of the head with a shot gun. He buries Mother and leaves town on the next train, not looking back.