Wise Blood is a masterpiece of allegory and farce (a blending of humor and tragedy). O'Connor takes issue with a world in which Jesus is but another moral man, in which the Incarnation is valid only to the unintellectual, and in which people can—through their own actions or natural goodness—save themselves. Published in 1952, Wise Blood is a compelling portrait of isolated characters in their search for spiritual truth.

The plot of the novel revolves around Hazel Motes, who returns after several years of service in the military to find his family home in ruins and the members of his family either dead or missing. Partially in response to this discovery, he travels to the city of Taulkinham and begins preaching a new gospel, the Church Without Christ, which advocates a humanistic reliance on self rather than on God.