After stalking and killing Roger, a ruthless but enthrallingly passionate mobster, Lestat is approached by Roger's ghost. Roger's ghost asks him to take care of his daughter Dora, a devout and popular television evangelist, whom he wants to spare from embarrassment. At the same time, Lestat has become increasingly paranoid that he's being stalked by a powerful force.

Eventually, Lestat meets the Devil, who calls himself Memnoch. He takes Lestat on a whirlwind tour of Heaven, Hell and retells of the entirety of history from his own point of view in an effort to convince Lestat to join him as God's adversary. In his journey, Memnoch claims he is not evil, but merely working for God by ushering lost souls into Heaven. Lestat is left in confusion, unable to decide whether or not to cast his lot with the Devil.

After the tour, Lestat believes himself to have had a major revelation. Among other things, he believes that he has seen Christ's crucifixion and that he has received Saint Veronica's Veil. He has also lost an eye in Hell. Even though Lestat suspects the entire experience was some kind of deception, he tells his story to Armand, David Talbot and Dora, who have joined him in New York City. When Lestat produces the veil as proof of his experience, Dora and Armand are deeply moved upon seeing it. Dora takes it and reveals it to the world, triggering a religious movement. Armand goes into the sunlight and immolates himself in order to convince people that a miracle has occurred.

At the end of the novel, Lestat and David go to New Orleans. There, Maharet returns Lestat's eye to him, along with a note from Memnoch that reveals Memnoch may have been manipulating Lestat to serve his own agenda. Lestat then loses control of himself and Maharet is forced to chain him in the basement of the St. Elizabeth's convent, which is owned by the vampires, so that he will not hurt himself or others.

Although the novel fits into the storyline of The Vampire Chronicles, the vast majority of it consists of Memnoch's account of cosmologyand theology.

The novel follows up on claims made by David Talbot in The Tale of the Body Thief that God and the Devil are on better terms than most Christians believe. It also reinterprets biblical stories to create a complete history of Earth, Heaven and Hell that fit neatly with the history of vampires given in The Queen of the Damned.