The Queen of the Damned is the third of Anne Rice's Vampire Chronicles. This fictional story is told in five parts. It chronicles the trials of a group of modern-day vampires locked in struggle to save the mortal humans from the first vampire, Akasha, who has awoken from six-thousand years of sleep with a plan to kill all the males on earth in order to usher in a reign of peace. Akasha has taken the mischievous vampire, Lestat, as her immortal lover. She's also destroyed all other vampires, except for a few of Lestat's close friends. In the end, the fulfillment of an ancient curse destroys Akasha, saves the mortals, and reunites Lestat with his loved ones.

Lestat, the devilish and charismatic vampire and star of the first two Vampire Chronicles, Interview with the Vampire (1976), and The Vampire Lestat (1985), has become a rock star and is planning a live rock concert in San Francisco in ten days. As a rock star, he openly admits to being a vampire and sings songs about the old vampire legends. This includes stories of Enkil and Akasha, known as the Mother and Father vampires. The mortal humans love him and think he is a human pretending to be a vampire, as a gimmick to sell albums. Most other vampires are threatened by his audacity. They've sent out the call to ambush and dismember Lestat at his live concert. The Queen, Akasha, has slept, unmoving, at her husband's side for as long as any vampire can remember. Now, she's suddenly awakened, drunk the last of her husband's blood, escaped her secret crypt and gone out into the world. She burns coven houses and vampires, as she goes.

The vampires who have not yet been killed, including many of Lestat's old friends from the previous novels, are drawn through fear, curiosity or love of Lestat to San Francisco for the concert. At the same time, all vampires around the world, and even some mortal acolytes, have begun having vivid tragic dreams about an ancient pair of red-haired twin sisters.

A mortal woman, Jesse Reese, has come to suspect that her red-haired Aunt Maharet is not human and may be the same kind of creature as Lestat. She, too, makes her way to the concert. There, she is killed by an angry vampire and turned into a vampire by Maharet, who is indeed a vampire. That night, Akasha burns all the vampires who have come to do Lestat harm. She then grabs Lestat and takes him away with her. All the surviving vampires gather at Maharet's home in Sonoma to decide what they should do.

Once there, it becomes clear that Akasha has spared them, because they are beloved by Lestat. It is also clear that Maharet is one of the red-haired twins from the visions and that it is her sister, Mekare, who has risen from sleep and is sending the visions to the others. They do not know how to stop Akasha, because she holds the original spirit and creator of vampires in her body. If she dies, all other vampires will also die.

Meanwhile, Akasha reveals her plan to Lestat, even as she drugs him into a love trance with her own ancient blood. She has realized during all her years asleep and listening to mortal thoughts that the only answer for true world peace is to kill all males and let women rule the world. Lestat tries to argue, but she is too strong for him. They make their way to Sonoma so that Akasha can convince the other vampires to join them or, failing that, kill them. Mekare makes a sudden appearance at the meeting, cuts off Akasha's head and eats her brain and heart, in order to take the life spirit of all vampires into her own body. The remaining vampires move to Miami and start a new coven.