When young history professor Russ is called upon by his sister to execute their late mother's estate, he is reunited with boyhood friend Mike, and with his father, the charismatic leader of a New Age cult. While exploring his memories, Russ wanders into a warehouse where hundreds of names are listed on the walls. As he sleeps that night, he dreams of a stone cudgel and awakens to find a cudgel in his motel room; the town drunk warns him that it is an instrument of sacrifice. A young liquor store clerk enlists him to help find her brother, whom she believes has been taken by the cult. Russ's aunt, who has been living in an asylum, tells him that his mother left a message hidden in her house.
Jeff Philips is working a dead end job at a call center. One day, an old man arrives at his apartment to tell him he is the last descendent of H.P. Lovecraft and must guard a relic to keep it from being reunited; if the pieces of the relic are united while the stars are in alignment, the sunken city of R'lyeh will rise from the sea and the demonic creature Cthulhu will be released upon an unsuspecting world.
For the first two acts, the plot essentially follows the lines of the short story. However, in the third act of the film, the protagonist, Wilmarth, uncovers an attempt by collaborators (or cultists) to open a gateway between Yuggoth and Earth. He foils the plot with the help of an added character, Hannah, the child of one of the collaborators. His escape, however, is unsuccessful and at the end of the film the audience discovers that Wilmarth has been narrating from a machine attached to the cylinder in which his brain now resides. This differs from the original story in which Wilmarth flees in the middle of the night and safely returns to Arkham.
The movie begins with stock footage of President Clinton and other people announcing the existence of the government experiment Project MKUltra. The scene then cuts away to camera footage of James Hirsch (Michael McMillian), a young man investigating Project MKUltra. With a friend filming him, James takes the drug used in the experiments, dimethyltryptamine-19 (DMT-19). Soon, bizarre music and voices begin to broadcast from a nearby radio and James becomes extremely anxious, announcing that something is coming towards the house and that it wants to "wear them". A large, shadowy figure rushes by the window and the camera's footage cuts in and out, ultimately ending with a shot of James with all-black eyes and a disfigured face.