In ALIEN: Fate of the Nostromo, players take on the role of Nostromo crew members Ripley, Lambert, Parker, Brett, or Dallas. Over the course of the game, they collect scrap, craft items, and fulfill different objectives. The crew lose and gain morale as they encounter the Alien and other situations. If crew morale reaches zero, players will lose the game.

Each turn consists of two phases. In the Crew Action phase, players will creep through the Nostromo's halls, gathering scrap, crafting items, trading scrap and items with other players, and using items and their special abilities. Brett, for example, can make items with one fewer scrap than other players. If the Alien is within three spaces of the player with the incinerator, that player may use the incinerator to send the Alien back to its nest.

In the Encounter phase, players will draw and resolve an Encounter card. The Alien could be lurking behind any dark corner...

Once the players achieve their initial objectives, they face one of five final missions, each with a unique set of requirements. Players must meet the final mission's requirements simultaneously to win the game. Players may also introduce Science Officer Ash for a more challenging game. Ash moves through the ship, taking scrap and forcing the crew to lose morale.