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. After college, he attends a Baptist seminary, and he is ordained as a Baptist minister. While managing to hide certain sexual indiscretions, he is thrown out of the seminary before completing his bachelor of divinity because he is too drunk to attend a church where he is supposed to preach.

After several years as a traveling salesman of farm equipment, he becomes a confidante of Sharon Falconer, a popular motivational speaker and evangelist with a "road church" show. Gantry becomes her lover, but loses both her and his position when she and scores of attendants are killed in a tragic fire in her tent tabernacle. After this catastrophe, he briefly acts as a "New Thought" evangelist, and eventually becomes a Methodist minister. He marries a local parishioner, although he is unhappy with her sexual frigidity, and uses her for appearances only. Years later the Methodist leadership awards him a larger congregation in Lewis's fictional city of Zenith. With his power and career in full tilt, Gantry manipulates local, state and national politics which involves police raids against bootleggers and bar patrons. His corruption and power hunger contribute to the downfall, physical injury, and even death of key people around him, including Frank Shallard, a sincere minister who questions the moral purpose of the evangelical church. Shallard, a former associate, is nearly beaten to death by a lynch squad of Gantry loyalists who were angered by his "atheistic" divergences in Christian teachings.

Especially ironic is the way he champions love, an emotion of which he seems incapable, in his sermons; preaches against ambition, when he is so patently ambitious; and organizes crusades against (mainly sexual) immorality, when he has difficulty resisting sexual temptations.

Gantry's career comes close to a major scandal when one of his tawdry affairs turns out to be a husband and wife blackmail scheme. Gantry manages to be extracted from his potential downfall by his close friend and political alliance with a powerful lawyer and private detective agency. A thoroughly repentant Gantry swears to abstain from his sinful proclivities but, true to form, notices a younger woman during his sermon.