The film starts with a sequence in which David (Chase Williamson) appears beheading an undead skinhead with an axe, and poses the question about whether an axe that had its handle and head replaced over time, is still the same axe. It then cuts to a Chinese restaurant, where due to the side effects of some "sauce", David describes having had wild hallucinations, but also seeming able to count the grains in a plate of rice, and know details about the rice's origin. At the restaurant, David meets reporter Arnie Blondestone (Paul Giamatti), who supposedly is to help David publish his experiences. The film then follows David's stories as told to Arnie.
First, Arnie cynically asks David whether he would describe himself as an exorcist. David tells him that the previous night he and his friend John (Rob Mayes) had attended a late night call from Shelley Morris (Allison Weissman)', who asked them for help, saying she was being harassed by her dead boyfriend. David and John had gone to the girl's house, but while they were talking, they realized they each were seeing different versions of her. When they confronted her with this, she crumbled into snakes, which ended up forming a monster from various meat products from a nearby freezer. The monster said it sought to battle its nemesis, TV show psychic Albert Marconi (Clancy Brown). The boys put the monster on the phone with Marconi, who promptly destroyed the monster over the phone.
Back at the restaurant, David, annoyed by Arnie's cynism, attempts to convince him of his abilities by describing the contents of Arnie's pockets, and predicting the outcome of ten throws of a coin. Arnie remains skeptical until David describes in full detail a twisted dream Arnie had the night before.
The tale then goes to the night when it all began, a rock gig two years previous, where John is playing with his band. There, David meets his friend Fred Chu (Jimmy Wong), and they witness Amy Sullivan (Fabianne Therese) being teased by wannabe-gangsta Justin White by taking her prosthetic hand away from her. Amy tells David that her dog bit some Jamaican guy and it has now gone missing. When the gig ends, David meets said Jamaican guy, who goes by the name Robert Marley (Tai Bennett), who despite David's skepticism, appears able to not only do strange tricks, but also knows about David's past and possible future. When David goes back to his truck, he finds Amy's missing dog waiting for him near it, which starts following David everywhere from that point on.
That night, David gets another late call by John, desperately asking David to come over to his apartment. Upon getting there, David finds John severely delusional, so he decides to take him to a hospital. Before leaving, David takes a syringe with a black liquid, assuming it is what John has been taking, and tucks it into his pocket. John then tells David that he seems to be losing touch with reality, and remembers calling David repeatedly, despite David saying he only got one call. John refuses to go to the hospital and explains that the liquid in the black syringe is called "soy sauce", that he got it from the Jamaican guy, and that using it has given him the ability to see the future and other dimensions. David is in total disbelief, but during the conversation, David's phone rings, and inexplicably it is John calling. David appears overwhelmed and John apologizes for everything that is going to happen.
They drive off, and John soon falls unconscious. Shortly afterwards, the syringe in David's pocket accidentally gets stuck into his leg, which causes him to begin having severe hallucinations. After David puts himself back together and drives on, a character named Roger North (Doug Jones) appears in the back of his truck. North appears to be from another dimension, and says he has been studying humanity and David. North tries to get some kind of giant leech on David. David struggles, and when he manages to get rid of the leech, North inexplicably disappears. A detective named Appleton then walks up to David's truck, and takes him and an unconscious John to the police station, where he questions David about what happened earlier that night. During the interrogation, David begins to notice he knows beforehand what Appleton (Glynn Turman) is going to say. Appleton is then called out of the room and when he comes back, he tells David that John has died.
Back at the restaurant, Arnie goes back to being skeptical and advises David to publish the story as fiction. David takes Arnie to his truck and shows him an initially empty cage. Instructed to look at the cage from the back of his eye, Arnie sees a raging monster resembling a Japanese spider crab, which appears to convince Arnie that David is telling the truth.
Cut back to the police station; Appleton leaves again, and David gets another call from John, who guides him into escaping the police station. Eventually, David goes to his own house, where he meets Justin White (Jonny Weston), who appears possessed by a demon called "Shitload". White tells David he must come with him to a mall, and after David resists, White ends up throwing him in the back of a van, where David rejoins with Fred, Amy and her dog, and the still unconscious John. The dog licks John's hand, which magically causes John to regain consciousness.
Once at the mall, White reveals a "ghost door" and explains that Amy is the only one who can open it. Appleton then arrives, kills White, and intends to take the four remaining people away, but as they are leaving, his head explodes, releasing the spirit of Shitload, which then goes into Fred Chu (Jimmy Wong). David shoots Fred and burns him with Appleton's car. They go back into the mall, and Amy opens the magic ghost door with her ghost hand. After David, John and the dog go through it, they meet North again, who reveals to have allied with Marconi. Marconi gives David and John a bomb they are to use to destroy an entity from another dimension named Korrok, which is the cause of all the anomalies they have been experiencing. When David and John enter the portal, they are told their coming was prophesized, that they are in a parallel universe in which Korrok a machine turned sentient apparently revolutionized society, at the expense of its detractors being slaughtered. They are taken to Korrok, and explained that since David and John appear to know how to cross planes, they are supposed to give that knowledge to Korrok by sacrificing themselves to it, so that Korrok's people can cross to their plane and continue to spread Korrok's greatness. After John fails to activate the bomb, it is the dog who ends up reactivating it and jumping into Korrok with it. Upon escaping, David and John meet Marconi, who explains to them that they were only recruited as escorts to the dog, and they were chosen because they would not be seen as a threat.
The scene cuts back to David and Arnie at the restaurant. David explains that the dog had become mentally connected with Marconi and North when it bit the Jamaican guy, and that Korrok was probably not destroyed. Arnie agrees to publish David's story, but during their talk David notices that Arnie's self-image does not match what Dave is seeing, to which David concludes that Arnie is a product of his mind. They go to Arnie's car and find Arnie's dead body in the trunk. They then assume that Arnie was killed shortly after he contacted David, to avoid David's experiences being published. Arnie gets really upset about being just a product of David's imagination, so David pops him out of existence.
During the end credits, David and John are seen playing basketball in a court, and a portal appears. They cross and they find themselves in a similar court in another strange dimension where two men arrive flying in metallic cones attempt to recruit them to save their universe too. They make an excuse and walk away, uninterested.