The game basically follows the same plot as Aliens: Colonial Marines, with some notable alterations.
A group of Colonial Marines reach the USS Sulaco 18 weeks after the Acheron (LV-426) incident. They discover the presence of Union of Progressive Peoples (U.P.P.) soldiers and a Xenomorph Hive aboard the ship. After their encounters with a Xenomorph Queen, the Marines ascend down to LV-426. There they discover that the U.P.P. are trying to harvest the Xenomorphs for their own use. The Marines eliminate the U.P.P. presence in the area and destroys their satcom. The squad then proceeded to escape the area in an APC as the Xenomorphs attack.
However, the APC crashes into the derelict, ending up inside the Pilot's chamber. There the Marines face off against a Jockey-Xenomorph, ultimately defeating it. The Xenomorph presence suggests that the Weyland-Yutani Corporation is involved. The Marines travel to a Weyland-Yutani research facility located on the Martian moon Phobos, where they discover a series of experiments being run on the Xenomorphs, including the creation of gorilla Xenomorphs and a giant tank-like Xenomorph. The Marines, knowing of the company's plan, returns to the Sulaco where they face off against a gigantic Queen (possibly the Queen Mother), with the Sulaco ultimately being destroyed.
- - One of four starter playable characters. Typical "Natural born leader" stereotype.
- - One of four starter playable characters. Typical "Rookie and inexperience" stereotype.
- - One of four starter playable characters. Typical "Hot-head woman" stereotype.
- - One of four starter playable characters. Typical "Gentle Giant" stereotype.
- - A teenage girl who became a Colonial Marine to stay away from her over-protective brothers.
- - A Marine who is well known from his good luck. He always survives wars and accidents that nobody else survives.
- - A Marine who came from a formerly wealthy family. Probably the most positive-thinking of the Marines in Infestation.
- - A con man and former gang member who choose to become a Marine to avoid getting a jail sentence.
- - Goth and Emo looking Marine who has a troubled past life.
- - A gun fanatic Marine who got the "Bonesaw" nickname from a past war when he used his M56 Smartgun to blow off a Marines leg (Possibly Jeremy Cruz from Aliens: Colonial Marines) after an APC was flipped over due a magmine.
- - A hacker and computer fanatic who became a Marine due to her hacking specialist. She often speaks computer words in her conversations.
- - A Marine who was rumoured to be synthetic.
- - A Marine who suffers from Posttraumatic stress disorder.
- - Last recruitable team member. Joined the Marines to follow in his father's footsteps and to try too be more successful than him.
- - The oldest member of playable characters
- Gorilla Alien
- Gorilla Alien Praetorian
- Unknown boss (possibly a Xenomorph Empress or a young Queen Mother)
- The game initially began development as a Nintendo DS version of Aliens: Colonial Marines, before being cancelled. However, when Colonial Marines entered production again, the DS version was finished and released under the new title of "Aliens: Infestation".
Aliens: Infestation was featured on the Feb. 25th episode of the video game documentary series "All Your History Are Belong To Us" on the Machinima YouTube network.