Tensions have been high with the alien "bug" races of the galaxy – the Zothren – and your ship has crash landed on the planet Hive IV, one of the more renegade "bug" planets. You quickly set up perimeter force fields and begin surveying the surrounding terrain for debris from your ship, only to find it scattered everywhere. Then you see them – at first only a few "bug" scouts, but then the numbers begin to increase all around you: archers, slashers, and even the monstrous brutes. This is more than a scouting party; this is a war party! They begin to attack the shields as the crew starts to retrieve debris. The SOS has been sent and a ship in the sector has responded, but can it get to you before the "bugs" overwhelm your crew? Can you repair parts of the ship and use it as a defense? Can you repair the hull and fire up the engine to lift off? It's all in the hands of the crew – your hands.

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.