Corporal Bower (Ben Foster) wakes up from hypersleep to find himself alone, with no memory of who he is or what happened to the crew of the 60,000-passenger sleeper ship, Elysium. He proceeds to wake up Lieutenant Payton (Dennis Quaid) who is also suffering from amnesia. They are unable either to access the ship's bridge or to communicate with anyone else, including the three-man flight crew team they are supposed to relieve. With the ship wracked by power surges from a failing reactor, Bower assumes he must be a technician automatically awakened by the principal on-board computer in order to affect repairs.
Bower begins exploring the spacecraft under Payton's radio guidance. Noticing odd physical symptoms, Bower talks with Payton about Pandorum, a psychological condition brought on by extended periods of deep-space travel and hypersleep. Its symptoms and effects include severe paranoia, vivid hallucinations, and homicidal tendencies. Payton recounts the story of another ship, the Eden, which was destroyed when a crazed member of the flight crew jettisoned 5000 hibernating passengers into space, killing them.
As Bower continues searching the ship - partially in hopes of finding answers, and partially to find his wife - he encounters dead bodies and fast-moving humanoid creatures. Escaping from one of the creatures, he encounters other survivors: Manh (Cung Le), a Vietnamese man working in Agriculture, and Nadia (Antje Traue), a genetic engineer safeguarding millions of samples of plant and animal life from Earth. All these samples will be destroyed if the ship's reactor fails.
On the flight deck, Payton discovers another crew member, Corporal Gallo (Cam Gigandet), who reveals that he was part of the flight crew that received the final message from Earth. He claims that his other two crew mates suffered from an onset of Pandorum, and that he had to kill them in self-defense. Payton is wary of Gallo, noting his strange behavior.