Narrated by Lestat, Blood Canticle finds young Mayfair witch and heiress Mona wasting away, victim to a mysterious disease brought on by the birth of her daughter. As the novel plays out, Mona and her guardian, Rowan Mayfair, reveal more and more about the powerful genetic plague that has haunted the Mayfairs for generations: their connection to the Taltos, an advanced species of human to which both women have given birth. Mona and the young vampire Tarquin "Quinn" Blackwood are in love. Lestat turns a dying Mona into a vampire so that the lovers can be together forever, also knowing that if Quinn had done it himself, he and Mona could not have delighted in sharing their most intimate thoughts as most vampires are capable of doing. It is an oft-articulated rule within Rice's Vampire Chronicles that "Fledgling" vampires and their "Makers" are forever unable to read each other's minds.

While trying to prevent Mona's family from discovering her transformation, Lestat falls in love with Rowan; secretly, she pines for him as well. As Mona adjusts to her new power, Lestat enlists the ancient vampire Maharet to help find Mona's Taltos child. Lestat, Quinn and Mona arrive at the remote island colony of the Taltos, but instead of finding a secluded utopia they discover that years of criminal intrigue and civil war have taken their toll. The remaining Taltos join the Mayfair clan at their New Orleans Mayfair Medical Center where they safely learn and grow and be together as a family.

Mona and Quinn are taken by Khayman to be properly instructed in the ways of vampirism by Maharet and Mekare. Rowan seeks out Lestat, half in love with him but torn by her love for her husband Michael; exhausted by her life, she requests that he give her the Dark Gift. Lestat declines, pained though he is, because she is a guiding force for the Mayfair family and he cannot take her away from it.