As with the first book in the series, the novel begins with a frame narrative. After over a half century underground, Lestat awakens in the 1980s to the cacophony of electronic sounds and images that characterizes the MTV generation. Particularly, he is captivated by a fledgling rock band named Satan's Night Out. Determined both to achieve international fame and end the centuries of self-imposed vampire silence, Lestat takes command of the band (now renamed "The Vampire Lestat") and pens his own autobiography. The remainder of the novel purports to be that autobiography: the vampire traces his mortal youth as the son of a marquis in pre-Revolutionary France, his initiation into vampirism at the hands of Magnus, and his quest for the ultimate origins of his undead species.

While very different from the first novel in the Vampire Chronicles, The Vampire Lestat has proved to be the foundation for a broader range of narratives than is possible from Louis's brooding, passive perspective. The character of Lestat is one of Rice's most complex and popular literary alter egos, and his Faustian strivings have a mythopoeic resonance that links the novel to a grand tradition of spiritual and supernatural fiction.