The novel begins when old Mason Tarwater dies. Prior to his death, he had asked his great-nephew, the teen-aged protagonist Francis Tarwater, to give him a proper Christian burial with a cross marking the grave so that his body would be resurrected on Judgment Day. Young Tarwater starts to dig the grave but suddenly hears a "Voice" in his head telling to him to forget about the old man. Tarwater obeys and gets drunk instead. When he returns from drinking, he sets the house that he and his uncle had lived in on fire, with his great-uncle's body still inside. He leaves for the city and gets a ride from a salesman, who drops him off at his uncle Rayber's door.
Rayber is amazed to see young Tarwater, whom he had given up on a long time ago after the young boy had essentially been "kidnapped" by the boy's great uncle to live in the country and be brought up a Christian. Tarwater is also greeted at the door by Rayber's young son Bishop, who (it is implied) has Down syndrome and low intelligence. Bishop was the child that Rayber had with Bernice Bishop, a meddlesome social worker known as "the welfare woman." Mr. Mason previously told young Francis Tarwater that the welfare woman was much older than Rayber and only able to give him one disabled child, and that God had mercy on the child by making him "dim-witted," which was the only choice he had to protect him from the evil parents. Old Mason Tarwater (the great uncle) had commissioned the young Tarwater to baptize Bishop at some point, in order to save the little boy's soul.
Due to this history, Tarwater is immediately put on edge when confronted with Bishop, but decides to stay with Uncle Rayber anyway. He doesn't think of Bishop as a human being and is revolted by him.
The three begin to live together as a family for a while, and Rayber is excited to have his nephew back in order to raise him like a normal, educated boy. But Tarwater resists his uncle's attempts at secular reform very much the same way he resisted his great uncle's attempts at religious reform. Rayber understands what Tarwater is going through. When he (Rayber) was only seven years old, old Mason Tarwater kidnapped him in order to baptize him, but Rayber's father rescued him before the old man could fully corrupt him.
After many attempts by Rayber to "civilize" Tarwater, and many attempts by Tarwater to figure out his true destiny (be it as a prophet, which was his great uncle's wish, or as an enlightened, educated modern man, which is his Uncle Rayber's wish), Rayber devises a plan to take Tarwater back to the country where the damage had been done in hopes that confronting his past will allow him to leave it. Under the guise of taking the two boys out to the country to a lodge to go fishing, Rayber finally confronts Tarwater and tells him that he must change and must leave the crazy, superstitious Christian upbringing that his great uncle corrupted him with. Tarwater, however, is not so easily convinced. While at the lodge, he meets up again with the "Voice" (the devil) who tells Tarwater to forsake his great uncle's command to baptize little Bishop and instead, drown the boy. One evening, Tarwater takes Bishop out on a boat to the middle of the lake, with Rayber's reluctant blessing. Rayber cannot see them on the lake but can still hear the voices faintly. Tarwater ends up drowning Bishop while at the same time baptizing the boy, thereby fulfilling both destinies simultaneously. Rayber realizes what has happened and faints, not out of fear for his son's life, but because he feels nothing at his son's death.
Tarwater runs away into the woods in order to go back to his great uncle's house to confront his demons once and for all. He eventually hitches a ride with another man, who entices Tarwater to get drunk. Tarwater takes the man's offer and passes out, eventually waking up naked against a tree, his clothes neatly folded beside him. He dresses hurriedly and sets fire to the area.
Burning his way through the forest, Tarwater finally makes his way back to his great uncle's old farm, where the house has been burned to the ground. Tarwater had assumed that his great uncle had been burned up with it, but Buford, a black man who lived in the area, had actually rescued old Mason Tarwater's body from the house at the beginning of the novel when Tarwater had gone off to get drunk and given the old man a proper Christian burial, just as the old man had requested that Tarwater do. Tarwater realizes that his great uncle's two main requests (that he be given a proper burial and that the little boy Bishop be baptized) have been realized, which convinces Tarwater that he can no longer run away from his calling to be a prophet. The story ends with Tarwater heading toward the city to "Go warn the children of God of the terrible speed of mercy."