Set in the late 18th century to the late 1980s, the story follows the 200-year-long life of the vampire Lestat de Lioncourt, and his rise from humble beginnings as impoverished nobility in the countryside of the Auvergne in France, to the cosmopolitan city of Paris, to become transformed by the Dark Gift into a vampire.

After escaping his family and running off to Paris with his lover and confidante Nicolas de Lenfent, Lestat is kidnapped and bitten by the reclusive elder vampire Magnus, who orphans him on the night he is made but leaves him with a tower fortress and a vast fortune. Lestat abandons Nicki for fear of causing him harm and shuns contact with his loved ones. Instead, he decides to shower them with gifts and riches from his new found wealth, as a means to compensate his departure from their lives.

Later, his mother, Gabrielle, arrives to say goodbye to him, herself dying of consumption (tuberculosis). In order to save her, Lestat transforms her into his first immortal companion. He later turns Nicki into a vampire after Armand kidnaps him and they begin to grow apart because of Nicki's sullenness; he later commits suicide by "going into the fire," from severe depression. Armand "shows" Lestat the history of how he was made by Marius. Compelled by the idea of Marius, Lestat leaves markings carved into rock in numerous places while traveling with Gabrielle, hoping that one day, Marius will see them and find Lestat. Whilst in Egypt, abandoned by Gabrielle, Lestat sleeps in the ground after being burned by the sun, and is recovered by Marius who takes him to his secret Mediterranean island. There, Marius shares his past with him, and shows him Those Who Must Be Kept, Akasha and Enkil, who are the progenitors of all vampires. Once Marius has given his warning to Lestat not to go see them again, and leaves on a short outing, Lestat takes Nicolas's old violin and plays for the King and Queen, awakening them. Akasha feeds from Lestat as Lestat feeds from her. Then, Enkil, furious at the intrusion, attacks and nearly kills Lestat, who is saved by Marius, and then sent away.

The book ends on a cliffhanger after Lestat's debut concert in San Francisco, and leads directly into the third volume, The Queen of the Damned.