The novel tells the story of a young, narcissistic, womanizing college athlete who abandons his early ambition to become a lawyer. The legal profession does not suit the unethical Gantry, who then becomes a notorious and cynical alcoholic. Gantry is mistakenly ordained as a Baptist minister, briefly acts as a "New Thought" evangelist, and eventually becomes a Methodist minister. He acts as manager for Sharon Falconer, an itinerant evangelist. Gantry becomes her lover but loses both her and his position when she is killed in a fire at her new tabernacle.
During his career, Gantry contributes to the downfall, physical injury, and even death of key people around him, including a genuine minister, Frank Shallard. Ultimately Gantry marries well and obtains a large congregation in Lewis's fictional Midwestern city of Zenith.