Interview with the Vampire opens in 1970s America, as an interviewer described only as "the boy" listens to a vampire tell his life story.

This first person account of life as a sanguinarian immortal begins in 1791. Louis, a disillusioned and suicidal young Louisiana plantation owner, meets the mysterious Lestat: dark, deadly, and a vampire. By exchanging blood with him, Lestat passes this "dark gift" of vampirism on to Louis.

Under his companion's watchful eye, Louis learns the ways of the vampire. He struggles with the morality of his undead lifestyle, feeling immense guilt and choosing to feed on animals whilst Lestat revels in nightly killings. Louis's plantation slaves grow suspicious of their changed master, and faced with a mob he flees to New Orleans with Lestat.

One night, a hungry Louis stumbles upon a dead woman and her orphaned daughter. Unable to resist, he feeds on the 5-year-old. He manages to restrain himself before killing her, but Lestat discovers what he has done. Thrilled that Louis is behaving more like a "real" vampire, Lestat brings the child to their home and encourages Louis to feed on her again. Once he has, Lestat, frivolous and always delighted by novelty, turns the child into a vampire. He names her Claudia, calls her their daughter, and treats her like a doll. Although horrified by Lestat's actions, Louis grows to love Claudia deeply.

As Claudia ages mentally and emotionally, her body remains that of a tiny child. She grows bitter, blaming Lestat for trapping her in this infant form. She resolves to murder him, poisoning him and cutting his throat. Louis helps her hide his body in a swamp.

Claudia and Louis decide to visit Europe in search of others of their kind. Before they can leave, however, Lestat returns to their home, having survived the attempted murder. Louis sets fire to the building and flees with Claudia, leaving Lestat to burn.

Although Louis and Claudia begin their search in Eastern Europe, where they encounter zombie-like animated corpses, they do not discover refined, glamorous vampires like themselves until they reach Paris. They visit the Théatre des Vampires, where the vampire Armand and his coven perform nightly for unsuspecting humans, feeding on them onstage.

Louis and Armand immediately form a deep emotional connection, but Claudia dislikes the coven and insists Louis create a mother vampire for her out of a Parisian woman named Madeleine.

This new family arrangement is short-lived. Lestat, having survived once again, arrives in Paris and informs the coven that Louis and Claudia attempted to kill him – a cardinal sin amongst vampires. Louis, Claudia and Madeleine are taken prisoner. Louis is locked in a coffin and left to starve. He is released by Armand, only to discover that Claudia and Madeleine have been locked in an open-roofed prison and burnt to death by the sun.

In revenge, Louis burns down the Théatre and all within. He and Armand travel Europe together but, haunted by Claudia's death, Louis eventually returns to New Orleans. Here he lives a solitary existence and, he tells the boy interviewing him, experiences great sorrow.

Despite this, the boy begs to be made a vampire. Furious, Louis bites him, but does not kill him. The novel ends with the boy heading out in search of Lestat, and the prospect of immortality.