Set near the fictional town of Derry, Maine, Dreamcatcher is the story of four lifelong friends: Gary "Jonesy" Jones, Pete Moore, Joe "Beaver" Clarendon and Henry Devlin. As young teenagers, the four saved Douglas "Duddits" Cavell, an older boy with Down syndrome, from a group of sadistic bullies. From their new friendship with Duddits, Jonesy, Beaver, Henry and Pete began to share the boy's unusual powers, including telepathy, shared dreaming, and seeing "the line", a psychic trace left by the movement of human beings. Jonesy, Beaver, Henry and Pete reunite for their annual hunting trip at the Hole-in-the-Wall, an isolated lodge in the Jefferson Tract. There, they become caught between an alien invasion and an insane US Army Colonel, Abraham Kurtz. Jonesy and Beaver, who remain at the cabin while Henry and Pete go out for supplies, encounter Richard McCarthy, a disoriented and delirious stranger wandering near the lodge during a blizzard talking about lights in the sky. The victim of an alien abduction, McCarthy grows sicker and dies while sitting on the toilet. An extraterrestrial parasite eats its way out of his body and attacks the two men, killing Beaver. Jonesy inhales the spores of the strange reddish fungus that the stranger and his parasite have spread around the cabin, and an alien entity takes over his mind.
On the return trip from their supply run, Henry and Pete encounter a woman from the same hunting party as the strange man at the cabin. She is also delirious and infected with a parasite. After crashing their car, Henry leaves Pete with the woman and attempts to regain the cabin by foot. From there, his telepathic senses let him know that Pete is in trouble, Beaver is dead, and Jonesy is no longer Jonesy. Mr. Gray, manipulating Jonesy's body, is attempting to leave the area. The aliens have attempted to infect Earth multiple times, beginning with the Roswell crash in the 1940s, but environmental factors have always stopped them, and the US government has covered up the failed invasion attempts every time. With the infection of Jonesy, who can contain the alien within his mind and also spread the infection, Mr. Gray has become the perfect Typhoid Mary—and he knows it. It becomes up to Henry—by now a quarantined prisoner of the Army—to convince the militaryto go after Jonesy/Mr. Gray before it is too late. Jonesy himself, now a prisoner in his own mind, tries to help. Both of them are convinced that their old friend Duddits may be the key to saving the world.