The film begins with Reggie (Reggie Bannister), running about in the desert, still on the trail of his nemesis - The Tall Man (Angus Scrimm). He then pays a man to offer him a ride, but realizes it's actually his car they're in, and the man stole it when he recalls putting a gun in the middle compartment. He chucks the man out almost totally naked, but two spheres suddenly fly by, and one sphere kills the man on the road while the other chases after Reggie. He manages to defeat them however, but then Reggie wakes up in a hospital sitting with Mike (A. Michael Baldwin) talking to him as he sits in a wheelchair, who apparently looks after him due to him having an early stage of dementia. He then tells Mike his story:
In an apparent alternate reality dream setting, Reggie meets a woman who mistakes him for a friend. Her car isn't working, so Reggie offers her a lift. They go to a cabin on a farm, and Reggie learns that a Bulgarian man named Demeter helps out. Reggie explains to her about his dealings with The Tall Man over the years, and she is amazed by his tale. He tries his usual lady wooing, but is turned down.
As Reggie plays a song on his guitar, he cannot remember her name, and goes to sleep. Later, The Tall Man shows up with more of his deadly spheres. A flashback scene then shows Reggie back in the hospital, with The Tall Man (or his actual identity, Jebediah Morningside) laying in the bed next to him. They then talk. Jebediah explains he's nearly finished, and has lost many friends. He says they're there basically to die.
Reggie wakes up the next morning on the farm, remembering the lady's name is Dawn. He gets no answer when he asks her a question, and finds that she's been killed by spheres, which then give chase. Reggie equips himself with a shotgun. The spheres force him into a nearby barn. A man armed with an axe confronts him, and it's revealed he is Demeter. A sphere kills a horse. Another sphere then manages to get inside the barn, killing Demeter, before Reggie fights it off. Meanwhile, Reggie speaks to Mike again in the hospital. Mike tells him about a new threat looming.
Back in his dream, Reggie goes through the woods. Along a path, he encounters a gigantic sphere hovering in the sky, and Reggie is back at the hospital again. Reggie alternates between the other world in both his dream, and the present time. The Tall Man appears, and says their paths cross again. Suddenly it's 1979; a younger Reggie will attend a funeral in Morningside, and that all his efforts got him nowhere. The Tall Man proclaims he can resurrect Reggie's dead family in exchange for him ceasing his meddling.
Reggie is next seen in a mortuary, contending with a dwarf "Lurker"; followers of The Tall Man, and the Lady in Lavender appears. She is shot by Reggie and seemingly killed. Continuing on, Reggie goes into a large cave, shooting a dwarf and the place shakes. The Tall Man asks him if he's considered his offer, but when Reggie retaliates, The Tall Man again reminds him his chances are depleting. Reggie wants his friends Jody and Mike back, but The Tall Man claims that he recognizes Reggie's "loyalty" for his friends as foolishness.
In yet another dream sequence which he alternates with the nightmare world, Reggie is strapped to a gurney as armed masked people appear. One is called Chunk and the other is revealed to be the person Reggie knew as Dawn despite her death, but she says her name is actually Jane and she thinks Reggie is delusional. She radios in some people. Reggie fails to convince her they know each other, but she gets him medical attention instead. More evil dwarf Lurkers show up to attack Reggie, but Chunk saves him and gives him a weapon. Mike reunites with Reggie soon thereafter. They then escape the nightmare hospital, but Mike says it's no longer their home, it's The Tall Man's now.
In the dream world, Reggie wanders around the hospital hallways, but a nurse orders him back to his room. In the nightmare world, an enemy has grabbed him. A spiked sphere then kills one of the people helping Reggie. Mike visits Reggie at the hospital, and says his dream orientates him. Mike reveals he had a dream too where he was in the desert, looking for Reggie. It turns out Mike still has his connection to The Tall Man, (from the previous film Phantasm IV: Oblivion). Mike reveals The Tall Man unleashed an alien virus that caused an apocalypse and killed most of Earth's population.
Jane is caught by The Tall Man, so Chunk, Mike and Reggie go after The Tall Man. In his own red planet world, they face and battle The Tall Man. Jane is killed. Chunk who posed as a dwarf then turns the tables. Chunk blows himself up to try to kill The Tall Man.
Back at the hospital, Reggie fights some Gravers alongside Mike. Jodie shows up in a car spewing bullets. After driving a while, they decided to drive north as The Tall Man hates coldness. In the hospital however, Reggie seemingly passes away, and the film ends.
During the end-credits, Chunk appears through a portal, missing a hand, and meets up with Rocky, (a survivor from Phantasm III: Lord of the Dead who helped Reggie). Chunk flirts with her, asking if he has a chance. Rocky teases back saying that there are no other guys around, but Rocky then sees Reggie and the others pulling up in the Barricuda vehicle and they get in. Lots of giant spheres are then shown in the sky, indicating the war with The Tall Man is far from finished.