Set in 1920s New York City, the novel depicts the elderly Harlem houngan PaPa LaBas and his companion Black Herman racing against the Wallflower Order, an international conspiracy dedicated to monotheism and control, as they attempt to root out the cause of and deal with the "Jes Grew" virus, a personification of ragtime, jazz, polytheism, and freedom. The Wallflower Order is said to work in concert with the Knights Templar Order to prevent people from dancing, to end the dance crazes spreading among black people. The virus is spread by certain black artists, referred to in the novel as "Jes Grew Carriers" or "J.G.C.s."
Historical, social, and political events mingle freely with fictional inventions. The United States' occupation of Haiti, attempts by whites to suppress jazz music, and the widespread belief that president Warren Harding had black ancestry are mingled with a plot in which the novel's hero, PaPa LaBas, searches for a mysterious book that has disappeared with black militant Abdul Sufi Hamid (whose name reflects that of the Harlem streetcorner radical preacher Sufi Abdul Hamid, a.k.a. Eugene Brown, an early black convert to Islam), as a group of radicals plans to return museum treasures looted from ancient Egypt to Africa, and the Atonists within the Wallflower Order are trying to locate and train the perfect "Talking Android," a black man who will renounce African-American culture in favor of European American culture. One of the supporting characters, an ally of Papa La Bas, is Black Herman (Bejamin Rucker, 1892–1934), an actual African-American stage magician and root doctor. Another touch of realism is the inclusion of a mysterious ocean liner that is part of the Black Star Line, a shipping line incorporated by Marcus Garvey, who organized the United Negro Improvement Association. Portions of the action take place at the "Villa Lewaro" mansion built by Madame C. J. Walker overlooking the Hudson River and at the Harlem townhouse of her daughter A'Lelia Walker, known as "The Dark Tower", located at 136th Street near Lenox Avenue. Other famous people who appear in the novel include the dance instructor Irene Castle, and the Harlem renaissance authors James Weldon Johnson, Claude McKay, Wallace Thurman, Countee Cullen, W. E. B. Du Bois, and a veiled reference to Malcolm X.
Additionally, in his project of blending the "real" and the "invented," Reed, through Papa LaBas, recites a counter history of The Bible, whose content transforms the normative understanding of Judeo-Christian roots. Featuring Osiris, Seth, Moses and other important figures in both Egyptian and Judeo-Christian mythology, Reed re-imagines an entirely alternate past, evidenced by the Templar conflict that takes place in the novel.