Prometheus begins on Earth. The Engineers arrive on the planet in the beginning of times. One of them drinks a black liquid that reduces him to DNA. He dissolves into water and creates the first cell, which initiates the evolutionary process of the human race.
In 2085, Dr. Elizabeth Shaw (Noomi Rapace) and Dr. Charlie Holloway (Logan Marshall-Green) find evidence that life on Earth was created by alien "Gods", and an identical pictogram in the ruins of countless ancient civilizations, that form a star map to the Engineers' homeworld, Paradise. The Weyland Corporation, represented by Meredith Vickers (Charlize Theron), decides to reunite a crew to travel to Paradise on the spaceship Prometheus and investigate. It includes Shaw, Holloway, Vickers, Captain Janek (Idris Elba), botanist Milburn (Rafe Spall), geologist Fifield (Sean Harris), Ford (Kate Dickie), Chance (Emun Elliot), Ravel (Benedict Wong) and a few others. An elderly Peter Weyland (Guy Pearce), Vickers' father and David's creator, secretly boards the ship, intenting to use the Engineers' technology to prevent his death and become immortal.
Five years later, Prometheus arrives on Paradise. The team leaves to explore the planet and finds an ancient temple. Fifield sends a series of probes to scan the place. David finds carvings on the walls that he is able to translate and uses them to acess the holographic database of the Engineers, using the knowledge he acquired to enter the room where he steals a vial containing the black liquid. Meanwhile, Shaw, Holloway and Ford find the last Engineer, who dies after a brief chase. He is beheaded by a door, and Shaw collects the head for further studies. just as Janek, who is in Prometheus, calls in to inform them that a storm is coming. Fifield and Milburn stay back while the others return to Prometheus. Janek informs Fifield and Milburn he'll send a rescue team by the morning.
David meets with Weyland, who orders him to infect Holloway with the black liquid. David does, and Holloway later learns that Shaw is infertile and they have sex. Meanwhile, Milburn and Fifield find countless dead Engineers and Fifield's probes direct them to the throne room, which is airtight. When they enter it, the atmosphere causes the urns containing black liquid to spill. A worm that had attached itself to Milburn's boot is exposed to the black liquid and mutates into the Hammerpede, that kills Milburn and infects Fifield.
The following day, the rescue team, which includes Shaw, Holloway, Ford, Chance and Ravel, arrives at the temple and finds Milburn dead and Fifield gone. Holloway's infection begins to affect him, and they decide to take him back to Prometheus, but Vickers refuses to allow him to come in. Holloway accepts his fate and asks Vickers to torch him with a flamethrower, which she does. Janek is infuriated by the turn of events.
That night, Janek notices that Fifield's helmet camera is on and recording Prometheus from the outside. Ravel goes to check the perimeter and is attacked by the mutated Fifield, who enters the ship and attacks the crew before being killed. Meanwhile, David learns that Shaw is infected and removes a Proto-Xenomorph from her, with orders from Weyland to freeze it and bring it back to Earth for further studies.
Shaw escapes after the Proto-Xenomorph is removed from her and learns of Weyland's presence. Shaw, Ford, David, Chance and Weyland return to the temple and find a ship called "The Juggernaut", which was armed with biological weapons that the Space Jockey, a pilot, intented to use to exterminate the human race before an accident with one of the Engineers' weapons of mass destruction damaged it and killed the Engineers. David awakens the Space Jockey and Weyland tries to beg for a cure. When Shaw tries to press for answers to why they intented to exterminate the human race, Weyland orders Chance to silence Shaw. This infuriates the Space Jockey, who believes humans were ultimately a failed experiment. He removes David's head, kills Weyland and Chance, and chases Shaw just as they're attacked by the Proto-Xenomorph, that kills the Engineer.
Shaw and David escape in another ship. David offers to coordinate Shaw back to Earth, but she refuses, claiming she needs to know the answers, and they decide to go the other way. Vickers is crushed by the Juggernaut's debris after Janek crashes the Prometheus against it to prevent it from taking off towards Earth. The Engineer, who had been impregnated by the Proto-Xenomorph during their fight, consulves as a Xenomorph bursts through his chest.