On the Red Planet in the year 2046, chaos reigns at the Olduvai Research Facility, owned by the Union Aerospace Corporation (UAC). An unseen horror lunges at scientists, dragging them into the darkness. Amidst the panic, Doctor Carmack (Robert Russell) sends a chilling transmission about a Level 5 security breach just as he witnesses a terrifying creature through a torn-open door.
Back on Earth, a team of eight dedicated Marines known as the Rapid Response Tactical Squad (RRTS) is poised for a much-anticipated leave, but their plans rapidly change when their squad leader, Sarge, receives urgent orders to investigate the catastrophic events at Olduvai, where all communication has ceased and 85 UAC employees are trapped. Despite Sarge's hesitation regarding John "Reaper" Grimm's (Karl Urban) involvement—given that Reaper's sister is on the Mars station—Reaper dons his gear regardless and joins the mission, eager to get to the bottom of the mystery.
The Marines are deployed using a teleportation device called the "Ark", recently uncovered in 2026, and they soon encounter Pinky (Dexter Fletcher), the unfortunate result of a botched Ark teleportation, who has been transformed into a two-wheeled engine due to the incident. The team eventually reunites with Dr. Samantha Grimm (Rosamund Pike), who shares critical information about their daunting task. It becomes apparent that the creatures on Mars are linked to humanoid remains containing a 24th chromosome, equipping them with superhuman abilities and remarkable healing powers.
As the Marines delve deeper into the facility, they discover a deranged Carmack and face off against deadly creatures determined to eliminate them. Each encounter heightens the stakes, leading to horrifying revelations about the altered genetics of the afflicted humans, and the resulting transformations into vicious monsters. The clock ticks as the team faces increasingly lethal threats, reducing their ranks after a series of brutal attacks by the monstrous inhabitants.
In a twist of fate, when an Imp escapes the Ark to wreak havoc on Earth, Sarge employs a weapon he fondly names the "Big Fucking Gun". The Marines confront a scene of devastation in a UAC facility back on Earth, leading to shocking decisions as they encounter non-infected survivors. The tension escalates, with insubordination met with brutal enforcement from Sarge, culminating in catastrophic personal sacrifices.
As battles ensue, Reaper finds himself gravely injured but given a second chance when Sam injects him with the 24th chromosome to save him. Instead of succumbing to monstrous transformation, Reaper emerges as a superhuman—a formidable force against the relentless onslaught of nightmarish creatures.
From there, the story shifts to a first-person shooter perspective, where Reaper battles through waves of enemies, including a grotesquely transformed Pinky, now a terrifying Demon. Once the dust settles and the chaos subsides, Reaper confronts the remnants of his team and learns of Sarge's own disturbing condition, linked to Carmack's fate.
In a tension-filled finale, as Sarge begins to morph into a creature of horror himself, a desperate struggle ensues. Reaper must make an agonizing choice leading to a thrilling climax: throwing Sarge into the Ark along with a grenade, obliterating them both. In the aftermath, Reaper rescues an injured Sam, holding her close as they make their way back to the surface, leaving the nightmare behind them.
