Gameplay of Aliens Infestation is comparable to the Metroid and Castlevania video games, where players are encouraged to search and backtrack for weapons, upgrades, and keys. The player controls one of a party of four marines and explores the U.S.S. Sulaco as well as LV-426 and Phobos in order to investigate the Union of Progressive Peoples (UPP) and Weyland-Yutani's involvement in Xenomorph development. If a marine falls in battle, another in the party will take their place. The player loses if the entire party is wiped out. Fallen characters can be replaced with any of fifteen displaced marines found throughout the game, each with their own unique dialog.
The USS Sephora has discovered the USS Sulaco adrift in space after the events of Aliens and Alien 3. You play as the Colonial Marines sent aboard the Sulaco to investigate and recover the life form detected aboard the ship.