While practicing motocross in Hawaii, Sean Jones witnesses the brutal murder of an important American prosecutor by the powerful mobster Eddie Kim. He is protected and persuaded by the FBI agent Neville Flynn to testify against Eddie in Los Angeles. They embark in the red-eye Flight 121 of Pacific Air, occupying the entire first-class. However, Eddie dispatches hundred of different species of snakes airborne with a time operated device in the luggage to release the snakes in the flight with the intent of crashing the plane. Neville and the passengers have to struggle with the snakes to survive.

While investigating a call in an abandoned house, Officer Frank Williams and a rookie find a woman brutally blinded, but they are attacked by a huge psychopath with an ax; the rookie is killed and Frank shots the criminal in the head, but has a severed arm. Four years later, the mutilated Frank is relocated, working as a guard in the County Detention Center. Frank goes with some delinquents to the Blackwell Hotel, an abandoned place since a fire burnt the last two floors, with the purpose of cleaning the location, preparing it to work as a shelter for homeless; in return, the criminals will have their sentences reduced. During the night, the inmate Kira that has some Christian tattoos in her body is kidnapped by the deranged serial-killer Kane that collect the eyes of his victims, while the rest of the group is attacked by the psychopath with his ax.