The year is 1930 in New Way City and there is a rumour going around of a monster - the "New Way Devil". A Predator is in town, looking for fame and glory by killing gangster boss Bruno Borgia. After stalking Bruno through the streets of the city, the Predator slays him in the museum. The Predator then finds Bruno's wife Isabella and their newborn baby son named Hunter. The woman shoots the Predator in the eye, spraying her and the baby in Predator blood. Now with only one eye, "Scarface" then tries to escape in a hurry, leaving its equipment behind which is later exploited by the humans. It runs through the city, now ravaged by riots against the police, trying to get back to its ship but an explosion leaves it incapacitated. Thinking that it would die, it sets off the ship's self-destruction device but fails to kill itself. Now with its race exposed, it is exiled onto a planet inhabited with deadly alien creatures.
Now 100 years later, the Predator clan that exiled it has come back to offer a chance of redemption for Scarface, because the humans have worked out how to use the Predator technology and the Predators are being slaughtered. The users of the technology - rival gang factions like the mafia, the Jamaican Serviteurs and the Matadores - exploit it to destroy their enemies. Ultimately, however, every faction pays tribute to Lucretia Borgia, the ruthless daughter of Hunter, who is the son of Bruno. The game occasionally switches between past and present, revisiting Scarface's battle against Bruno 100 years prior.
At the end, it is revealed that the computer that controls the city along with Hunter, MOTHER, is in fact Isabella, kept alive all these years by the Predators blood. Then, it is discovered that Hunter has gone through massive genetic augmentation, and has become a grotesqe hybrid of human and Predator. The game ends with an intense final battle between Scarface and Hunter, which Scarface wins, and he claims Hunters head as a trophy. A Predator ship then appears, and it is left unclear what they do with their disgraced comrade (it is implied that they took him back to the homeworld).
The game makes several attempts to tie up loose ends between the Alien, Predator and Aliens vs. Predator movies. A conversation between Lucretia and Hunter reveals that he knew Charles Bishop Weyland "before he disappeared"; Weyland was portrayed in Alien vs. Predator, being killed by a Predator. Also referenced in this conversation is the Yutani Corporation (who supposedly co-founded Weyland-Yutani corporations with Weyland, this is tied up convincingly) and MOTHER, the AI in the Nostromo in Alien. Several various other links and references are made throughout the game. A appearance of the Aliens is also made within the game.