The storylines of the three player characters are independent of one another. As an Alien the player must defend the Alien hive from human marines, then stow away on an evacuating spacecraft and reach the marines' ship, the Ferarco. When the Ferarco's self-destruct system is activated, the player must reach the escape shuttle, which takes them to Gateway Station. Here the player explores the station and battles more marines, reaching a ship departing for Earth. Before boarding the ship the player battles two Predators, after which the Alien enters the Earth-bound shuttle.

When playing as the Colonial Marine, the player begins at a research station on LV-426 built to study the derelict spacecraft where the Nostromo crew first encountered the Alien eggs in the film Alien (1979). Aliens attack and the player must fight their way through the research facility, the derelict ship, and an adjoining colony. Next the player explores the atmosphere processing station and shuts down its cooling valves in order to cause an explosion which will wipe out the Aliens. The player character escapes in a drop ship and travels to Odobenus Station in orbit above the planetoid, where they battle more Aliens, Predators, facehuggers, and cybernetically-enhanced Aliens until reaching the spaceship Tyrargo. Aboard the ship the player battles more enemies including an Alien/Predator hybrid and "praetorian" Aliens. The player then battles an Alien queen, defeating it by expelling it through the airlock.

The Predator character's storyline visits three different planets, beginning with the player hunting marines in order to recover a captured Predator ship and its occupant from a human military base. Aliens are accidentally released in the base and the player discovers that the humans have created an Alien/Predator hybrid by implanting the captured Predator with an Alien embryo. The player defeats the hybrid, triggers the facility's self-destruct mechanism, and escapes in the Predator ship. The player next visits Fiorina "Fury" 161, the prison planet that is the setting of Alien 3 (1992), where more Aliens and marines are battled. Finally the player visits a marine-controlled Alien habitat, battling cybernetically-enhanced Aliens, "praetorian" Aliens, and finally the Alien Queen.