Charles Dexter Ward is a young man from a prominent Rhode Island family who has disappeared from a mental asylum. He had been incarcerated during a prolonged period of insanity, during which he exhibited minor and inexplicable physiological changes. His empty cell is found to be very dusty.
The bulk of the story concerns the investigation conducted by the Wards' family doctor, Marinus Bicknell Willett, in an attempt to discover the reason for Ward's madness and physiological changes. Willett learns that Ward had spent the past several years attempting to discover the grave of his ill-reputed ancestor, Joseph Curwen. The doctor slowly begins to reveal the truth behind the legends surrounding Curwen, an eighteenth-century shipping entrepreneur and alleged alchemist, who was in reality a necromancer and mass-murderer. A raid on Curwen's farm is remarkable for the shouted incantations, lights, explosions, and some not-quite-human figures shot down by the raiders. The raiders soon swear any witnesses to strict secrecy about what they may have seen or heard.
As Willett's investigations proceed, he finds that Charles had recovered Curwen's ashes, and through the use of magical formulae contained in documents found hidden in Curwen's home in Providence, Rhode Island, was able to call forth Curwen from his "essential saltes" and resurrect him. Willett also finds that Curwen, who resembles Charles enough to pass for him, has murdered and replaced his modern descendant and resumed his evil activities. Although Curwen convinces onlookers that he is Charles, his anachronistic mindset and behaviour lead authorities to certify him insane and imprison him in an asylum.
While Curwen is locked up, Willett's investigation leads him to a bungalow in Pawtuxet Village, which Ward had purchased while under the influence of Curwen. The house is on the site of the old farm which was Curwen's headquarters for his nefarious doings; beneath is a vast catacomb that the wizard had built as a lair during his previous lifetime. During a horrific journey through this labyrinth in which Willett sees a deformed monster in a pit, Willett discovers the truth about Curwen's crimes and also the means of returning him to the grave. It is also revealed that Curwen has been engaged in a long-term conspiracy with certain other necromancers, associates from his previous life who have somehow escaped death, to resurrect and torture the world's wisest people to gain knowledge that will make them powerful and threaten the future of mankind. While in Curwen's laboratory, Willett accidentally summons an ancient entity who is an enemy of Curwen and his fellow necromancers. The doctor faints, awakening much later in the bungalow. The entrance to the vaults has been sealed as if it had never existed, but Willett finds a note from the being written in Latin instructing him to kill Curwen and destroy his body.
Willett confronts Curwen at the asylum and succeeds in reversing the resurrection spell, returning the sorcerer to dust. News reports reveal that Curwen's prime co-conspirators and their households have met brutal deaths, and their lairs have been destroyed.