A mafia drug lord has unleashed a new, highly addictive stimulant on the streets called HT25, derived from sharks held captive in a secret lab, and which causes monstrous side effects. After an explosion and leak at the lab, an army of mutated, bloodthirsty sharks and other creatures are set loose on the world.

The ultimate battle against the Amityville curse begins after the infamous murder house is exorcised from Earth and reappears in outer space in Amityville in Space.