The film begins in space with title cards appearing, referencing the technological evolution of space travel. Along with the population on Earth growing to the point of it exceeding the carry capacity and humanity has fought over the last natural resources. In the year 2174, a ship called Elysium is launched. In space, we see the massive ship flying towards the stars. On the bridge of the ship, officers receive a message from Earth. The message is "You're all that's left of us. Good luck, God Bless, and God speed".
Bower (Ben Foster) wakes up from his hyper-sleep pod and panics from claustrophobia due to being in a closed space. He manages to free himself from the pod and rips out the tubes going into his body. He sees that he has a series of numbers tattooed on his arm. After peeling away his dead skin, he sees that he is alone. Not knowing what's going on, he finds a locker with his name on it and puts on some clothes. He finds a picture of a woman. He notices a couple of other pods nearby. A pod for Cooper is empty. Another pod still has Payton (Dennis Quad) inside. Bower tries to wake Payton up by slamming something against the sealed pod, but he hardly makes a scratch on it. He tries to open the door of the room but it's locked. A power surge shakes the ship, causing Payton to wake up. Both men are suffering from memory loss due the General Anesthesia they received in hyper-sleep and can't remember what the mission is nor the destination. Payton is a Lieutenant and Bower is a Corporal. They realize that something's wrong since they're all alone. The numbers tattooed on their arms indicate which group they belong to. Another power surge shakes the ship and Bower realizes that he's an engineer. Something's wrong with the reactor and he needs to fix it. Payton gets a nearby command center working by using the auxiliary power. He tries to call for help but no one answers. They hear a noise coming from a nearby vent.
Payton decides that they need to find the crew members and get to the bridge to see what's happening. He sends Bower to find a way out in the vents while he stays behind at the command center to guide him around the ship. The vents are filled with tubes and are hard to crawl through. Bower tries to find his way to another room but the vents look endless and run in every direction. After feeling like he's going in circles, he panics and becomes claustrophobic again. Payton via radio calms Bower down by joking that he got the door open. Bower falls down a shaft and lands face-first on a grate. The fall causes him to lose contact with Payton. Bower lights a glow stick and sees Cooper's decomposing corpse right next to him. He falls through the grate and ends up in a storage compartment. Bower gets up but still can't communicate with Payton. The ship's corridors are long and dark.
While searching around, Bower comes across a woman, (named Nadia in the credits), trying to open a door. He tries to talk to her, but she quickly runs away. While chasing after her, he sees that she has seemingly stopped in a corridor. He tries to tell her that he's part of the crew and he needs to know what's going on. She remains silent. He shines his light on the figure and sees that it's not a woman but a man; a man who has been hung by his neck and is his stomach is cut opened. The woman pops up and attacks Bower, mugging him at knife point. She holds him down, taking his supplies, and orders him to remove his shoes as she only has toeless socks on her feet. She threaten to gut him if he resists. But suddenly they both hear screeching nearby.
Nadia runs away and Bower is left confused. He sees a blue light at the end of the corridor and the screeching gets louder. The blue lights are blow torches attached to spears carried by pale, scar covered, and armor wearing humanoid creatures (called The Hunters in the credits). The half-eaten man is pulled up and devoured. Bower runs back to the room he came through and hides in the storage compartment. While the creature looks for him, Payton's voice comes through the radio. The creature tears open the compartment and snatches Cooper's body. After the creature leaves, Bower is scared, telling Payton that something not human is on-board the ship.
Their memories start to return and remembers the mission. Payton says that there is no rescue nor turning back and turns out that the Elysium is not hauling cargo but that they are the cargo. The destination was Earth-like planet called Tanis which was one way ticket to colonize. The crew has been split into groups/shifts to work with 60,000 passengers on board. At the end of a groups turn (a couple of years), they are supposed to wake up the next group and debrief them. Bower also gets a childhood flashback remembering Tanis being discovered, watching it on television with his family being inspired by the idea of sending people up there. Bower then remembers his wife and that families of the crew were allowed to travel on the ship. Bower stops being scared and becomes desperate to find her before the creatures do. He also remembers that Payton has a wife as well. Payton tries to be the voice of reason and convince him to continue making his way to the reactor. If Bower can fix it, the power will come back on for the ship and they can implement security measures.
Bower looks around and finds a security room. He finds a non-lethal anti-riot gun which Payton says is deadly up-close and straps it to his arm. He goes into the corridors again and sees a hanged man. He thinks that he's going crazy since it looks like the same hanged man from before. However, upon closer inspection he finds that the man is different (he's still alive and in one piece). Bower cuts him down and is introduced to Shepard (Norman Reedus). Shepard is part of another group and has been by himself for a long time. Bower says that his commanding officer want's to know what's happening. Shepard says that there's no commanding officer and covers himself in oil to cover his scent from the creatures. He tries to leave but sees blue lights coming towards them. The creatures chase Bower and Shepard through the ship. The creatures are fast and have sharp weapons. They eventually string Shepard back up and Bower tries to shoot the creatures in order to save him, but his shot is blocked by a glass door. The creatures cut Shepard's stomach open, feeding on him, and they notice Bower which results in a chase. He runs into a man (named Mahn in the credits), who helps him escape from them but loses communication with Payton. Bower thanks him but can't understand Manh's language but still manages to communicate that he's part of the crew. He sees Manh's tattoo and sees that he's part of the agriculture crew. He tells him that he's going to start up the reactor and tells Manh to stay put. Meanwhile, Payton starts to get a bloody nose and gets increasingly scared that he can't talk to Bower.
Bower finds a housing container that acts as a living quarters. He sees that there are several other containers as well and food. Bower is attacked by Nadia again, making fall from a great distance. However, instead of gutting him like she said she would, she shows sympathy by asking if he is okay, then Manh pops up to defend Bower again. As Nadia and Manh fight, Bower fires off a shot into the air. He acts as the voice of reason, telling her that he understands that its felt like "every man for himself" and she wants to survive, but solidarity is the far more effective survival strategy. Bower tells Nadia that they need to start the reactor or else they'll lose everything, but she says that no one has ever came back from going that far down. Bower asks who she is but Nadia acts aloof, saying "nobody". She is a very cynical woman and doesn't trust him, putting a knife to his neck when he touches her. But eventually agrees to show him the way to the reactor after founding out he is apart of the flight crew(whom she thought was all dead) as he could fly the ship and land it.
They come across a hallway with water dipping from the ceiling and find themselves surrounded by creatures. A power surge shakes the ship, allowing Nadia to activate a door open. The creatures close in on them and Mahn holds up his spear unwilling to go down without a fight. They barely make it inside and seal the door where reveals some more about herself. Nadia has been awake for months and there use to be five of them that protected this room. To them it seemed worth protecting as it's an Embryonic chamber holding livestock and wildlife re-population that holds the world they are going to live in, stating that the ship is a Noah's Ark. She is a former biologist from Germany who spend seven years working for the Brandenburg Institute genetic sampling team collecting and readying earth's biosphere for the trip to Tanis. Her motive for enlisting on the mission was because she was a workaholic and it didn't felt right handing off the genetic samples so she volunteered to go along with it. She pours her heart out and broods about her amnesiac state, saying that she can remember the vault and its systems but she can't remember where she grew up or her brother's name. As a quirk she practices entomophagy, where she eats grasshoppers stating that it is good for protein and offers Bower some. He accepts and they eat together which disgusts Mahn.
After a while, Nadia leads the team through a part of the ship that holds civilian pods, telling them to keep quit and not slow her down. Bower notices that the majority of the pods are empty. Nadia tells him that it's the creatures hunting ground and tells them to hurry. Bower wonders if his wife is there, but Nadia tells him that the families of the crew are held in another area of the ship. Mahn gets distracted by something and holds his spear up. Bower quietly tells him to move but he don't, knowing something is following them. Nadia coldly says that they should leave him behind as he is slowing them down. Bower objects at first but he has no choice but to keep moving.
Bower suddenly disappears. Nadia walks over to where he was and falls down a grate. Bower lights up a glow stick and they both see that they've fallen into a massive pit of bones and gore. The creatures appear above the grate and move through the area. Bower climbs out of the pit first but keeps Nadia at bay. While he looks around, he's attacked by a creature. Bower is thrashed around while suffering from Pandorum and Manh comes to defend him again. He stabs the creature in the head, but it's still alive. Nadia manages to stab it in the leg but is thrashed around as well. Bower manages to stab it in the chest, and the trio repeatedly stab it until it's dead. The other creatures were watching and their leader gives them a case to run. It roars to its mates and some jump on the defeated creature and begin to devour it while others give chase to the trio. They come into another area and witness a man wake up from his pod. Bower attempts to help him but is too late as the man is stabbed in the head and eaten by the creatures. However, they mention to escape.
Meanwhile, Payton continues to hear more and more noise coming from the vent. He grabs a pipe and climbs up. As he enters the vent, through the mass of hoses and wires, he sees a human arm reach out for him. Gallo is naked and covered in blood/slime and Payton pulls him through and locks the vent. Gallo says that he came from the bridge before passing out.
The group appear to be lost and Bower complains that he thought Nadia knew where they were going. Nadia then irritably tells him that she was just trying to save their lives. They then take refuge in a room covered in algae and seal the door shut. Back to Bower and his team. They find that they are not alone. A hermit(named Leland in the credits) has been living in the room for years now. Leland is situated on a balcony above the team so that they can't reach him. He makes them some food which made with the algae and welcomes them to his home.
Back to Payton; Gallo is passed out. Payton inspects his arm and sees that he's part of the previous group. Gallo wakes up and asks Payton what he's doing. Payton asks where they are and Gallo states that all the stars look alike, that they are lost in space. Some of the blood on Gallo is from someone else, which makes Payton suspicious. Gallo says that he was with two other crew members, but they suffered from pandorum (i.e. space madness) and he was forced to kill them. Payton loads a needle gun with a shot to calm Gallo down, but he refuses to take it and becomes hostile. He accuses Payton of having pandorum and insists that he is the one who needs the shot instead.
Meanwhile, Nadia tries to clean her cut wounds that she received from their battle with pieces of her dirty clothing. Bower shows concern and asks if it is safe to clean herself with that. But Nadia sarcastically responds with sass saying that its nothing compared to facing those things. This leads to them having a conservation about what they are where Bower jokes about them being Aliens to lighten the mood. She tells him her theory that the creatures are actually passengers. In all the hyper-sleep pods, everyone was supplied with an accelerator to speed up adaptation and jump evolution to adjust to the conditions on Tanis. Instead, it could have made some people adapted to the ship. However, Bower questions why they nor Leland (who has been awaken for years) hasn't adapted at all. Nadia believes that the creatures may have been on the ship far longer than any of them.
Gallo tells Payton how Pandorum causes extreme paranoia and how it has an emotional trigger. What caused it with his crew is that Earth had mysteriously vanished and the thousands of people on the ship are all that's left of humanity - Leland tells the team what happened afterward based on accounts of other passengers and drawings depicted on the walls in his lair. Leland states that he "would grow into manhood" and Gallo is depicted with something abnormal with his mind as electric sparks appear around his head and blood is drawn around his noses. This strongly hints that he developed Pandorum. This strongly hints that had awaken other passengers to play "nasty little games" as he puts it. He would be their master or slayer to them, both "God and the Devil" as that is what some would say. He would send those who had behaved to exile themselves in the cargo hold to play nasty little game. This game involved them performing similar activities to that of the Hunters, where they hung each other on ropes, cutting their stomachs open, and cannibalizing each other. The drawings depicting the events show these passengers grabbing their heads as blood pours from their noses and electric sparks appear around them. Which suggests that Gallo drove them mad and Pandorum was the cause of the cannibalistic behavior on the ship. Eventually he went back into hyper-sleep. As he slept, a whole new world of evil grew as Leland puts it. Then the group is gassed by him while Gallo watches Payton go mad from the truth, waiting...
Bower wakes up to find himself, Nadia, and Manh hung upside down in the room. Leland is a survivalist who plans on eating them for food, which he has been doing for years with both human and the creatures. Nadia mouths off and Leland stabs her in the chest. He's about to fillet her when a power surge shakes the ship. He states that with Earth gone and the ship not working, there is nothing else left to live for than to go by his survival instincts and he wouldn't have survived this long if he had a heart. It's just survival of the fittest now, or maybe the brightest, as he puts it. Bower tells him that it was the last power surge. If they don't start the reactor within the hour, everything in the ship will shut down for good. Bower says that he understands why Leland is doing what he is doing and that no one was going to judge him, with Leland showing remorse for what he has done for all these years. Leland cuts them down and makes them walk through the ship at gunpoint with Bower's weapon.
Meanwhile, things get heated with Gallo and Payton. Gallo thinks that they should evacuate the ship while they still can, but Payton is confident that Bower will fix the reactor. Gallo insists that Payton is starting to exhibit signs of pandorum. Payton says that Gallo is crazy and continues to order him to "stand down".
The team comes across a hunter child feeding on algae covering the ship which Mahn tries to kill but Nadia stops him confusing it for human and it alerts other hunters. They escape to a part of the ship that holds the pods for families of the crew where all of them appear to be empty and Bower believes that they are all dead. Nadia appears to have warmed up to Bower after he saved his life and cares about him founding his wife, asking him if he thinks that she is here somewhere. But he remembers that the woman in the photo is no longer his wife and isn't on the ship. She left him and he had nothing left on Earth, so he signed up to be the engineer on the mission to found a place in history. This means that she vanished along with Earth. Out of empathy Nadia, tries to give emotional support to help him remain optimistic by saying she saved his life by leaving him. But he is so consumed by grief he becomes pessimistic, believing that there is nothing left to go back, which almost makes him give up on the mission. But Nadia continues to be optimistic and gets him motivated again by saying they were meant to go on and they were meant to survive, and now it's more important than ever. Bower than sees the pod for Paytons wife and remembers her name. He also remembers something else about Payton....
The team makes it to the reactor but find that below it is the sleeping ground for the creatures. Bower tries to walk across a catwalk to the reactor but it gives way. Manh holds onto the catwalk while Nadia runs across to help Bower. Seeing that Manh can't hold the weight of both of them, Bower allows himself to fall down to where the creatures are. Bower covers himself with skin/slime so that the creatures won't pick up his scent. He then crawls amongst them to get to the ladder leading up to the reactor. Once he gets there, Leland accidentally drops a light down to where the creatures are, waking them all up. Leland runs away while Manh drops the catwalk, crushing a couple of creatures. He makes noises and leads the creatures away from Bower & Nadia. Bower climbs up to the reactor and turns on the power, which fries some creatures in the process.
Gallo takes control of the needle gun and forces Payton to open his pod. Gallo has Payton start the ejection sequence and gets inside. However, Payton tricks Gallo and instead just locks him inside the pod.
Elsewhere, Manh manages to elude the hunters but then runs into the leader. Mahn is again unwilling to go down without a fight. The leader notices this and tosses him a spear to fight back with but the fight is mostly one sided. The leader pins Manh against a wall and starts to eat his stomach. Manh grabs a knife and repeatedly stabs the leader in the head until it dies. Manh then turns around to find it's child staring at him. He contemplates killing the child, but lowers his knife. The child in turn slices Manh's throat open. Bower turns on the reactor, providing power to the ship (which opens the door to the bridge). Payton is happy that Bower succeeded, but then finds that Gallo has escaped from his pod. Gallo attacks Payton and they fight for control over the needle gun. During the fight, their arms merge together. It's shown that Payton is the only person there and has been fighting himself. After Payton stabs himself in the leg with the needle, Leland winds up in the command center. Payton promptly fires the needle gun into Leland's eye killing him.
Bower and Nadia make it back to the bridge while being chased by cannibals. They lock the door and find Payton already there. Bower knew Payton's wife and knew the real Payton. It's revealed that "Payton" is actually Gallo! He was interacting with a younger version of himself (how he looked when he first started working on the ship) playing mind games with himself like he did with the passengers. Bower remembers what the real Payton looks like and knows that Gallo is the "God & Devil" from the story. When he went back to hyper-sleep, he got into Payton's pod instead of his own. Gallo says that doesn't remember what life was like before the flight and the ship is all he has left. Bower asks Gallo where exactly they are. After opening the window shields, all they can see is darkness and Bower panics from claustrophobia feeling that there is no escape. This, the revelation of the fate of Earth, and his ex-wife is too much for Bower and the effects of Pandorum start to catch up to him.
It's revealed that Gallo has became so paranoid that has has turned into an antihumanist. Because human civilization had ruin Earth's resources with overpopulation, he has come to believe that moralistic altruism is petty and life eating life like in the wildness is perfect. He tells Bower that with the ship they can create a new world with the ship (alluding to Nadia's theory) but in a wild primitive state. Meaning that he purposefully created the creatures that now roam the ship. He now attempts to exploit Bower's descent into madness like he did with the paranoid passengers and convert him to savagery.
It turns out that Gallo was lying earlier about them being lost in space. The flight log shows they have been on the ship for 923 years and realize that Elysium has been on Tanis the entire time, crash-landed in an ocean underwater. The creatures are not the passengers, nor did the passengers mutated but instead they are their descendants who evolved into a new species after generations of ecological selection, continuing the game Gallo had started with their ancestors as tradition. Gallo then attacks Bower but Nadia tries to stop him but due to her injury she is overpowered. Bower hallucinates about creatures trying to break into the bridge. Then Nadia sees fish swimming past the ship. Gallo begins to press Bower's face against the chair until he finally succumbs to Pandorum and Nadia tries to defend him. But due to her stab wound Gallo throws her off and advances on her with her own knife. Bower, still hallucinating, shoots a compartment (thinking a creature is coming through), causing a piece to crack the window. Nadia calls out to Bower snapping out of his delirium and he grabs her just in time before the windows break from the water pressure, flooding the ship with water. They run off and Gallo drowns along with cannibals.
Bower and Nadia run back to Bower's pod. They both get in and seal the door shut, but a lot of water gets in as well. Bower lets Nadia have his air mask while he almost drowns. The pod pops out of the surface of the ocean. Bower and Nadia survive and look around the alien planet. Bower comforts her telling her that it's safe to awake up now and she smiles. The ship, experiencing a hull breach, enacts the evacuation plan and ejects all the remaining pods. Soon the rest of the pods pop out of the ocean and the remaining people start to wake up. Bower smiles and puts his head on Nadia's in relief that they have completed their mission.
The film ends with text, stating that the population on Tanis year ONE is 1,213 humans. Bower had found a place in history.