In Alien Uprising, the player crew must either hold off the Zothren attacks until the rescue ship arrives, or repair the ship and lift off from the hostile planet before being destroyed. To achieve either of these goals, the crew must work together, using their unique skills and chosen actions to perform a number of tasks, defend themselves, and retrieve and repair equipment and the ship.
To establish the actions available each turn, the first player rolls custom dice, then each player chooses an action for the turn, starting with the first player. The available actions include combat, engineering, reload/recharge first aid, scout, and wild; the dice also have an alien icon that shows the speed of the enemy while limiting the actions that players have available to them. Players also have unique character skills, and the game can be set to higher levels of difficulty for more experienced players.