The story of Prey 2 had been narratively tied to the first game.

In Prey, an alien spacecraft called the Sphere appears over the southwestern portion of the United States and starts abducting humans and other objects as part of its cycle to sustain its resource supply and its organic crew. One of those abducted is Domasi “Tommy” Tawodi who, in part due his spirit guide from his Native American background, is able to navigate the Sphere, defeat hostile alien forces, and succeed in freeing captive humans and other lifeforms from the intelligence that controls it, before returning to earth.

Prey 2 was to focus on U.S. Marshal Killian Samuels, who starts the game on a passenger flight which suddenly crashes onto the Sphere, shown during the events of Prey. At the end of a short battle with some aliens he is knocked unconscious, after which the plot jumps forward several years. Samuels is now a bounty hunter on the alien world Exodus. Though he is aware of his profession and has retained his skills, he has no memory of what happened in the time that passed since his abduction. He initially believes himself to be the only human on Exodus until he runs into Tommy, whom he has apparently met in the period he no longer remembers. Killian then resumes his bounty hunter activities while recovering his memory. Some of the game’s audio logs, published by the Museum of Play, suggested that Tommy and Killian team up to fight common foes, some which are enemies that Tommy had made from within the first Prey.