In 2009, Graeme Willy and Clive Gollings (Simon Pegg and Nick Frost) are two English comic book nerds and best friends who have travelled to America to attend the annual Comic-Con convention and to take a road trip in their RV to visit all the sites of major extraterrestrial importance. At night along the highway they investigate a crashed car and they meet and discover an alien named Paul (voiced by Seth Rogen) who is in desperate need of their help.
Although shocked by the appearance of Paul, Graeme agrees to give Paul a ride, but Clive is not happy about the idea. Later, Lorenzo Zoil (Jason Bateman), a shady government agent, arrives at the site of the crashed car and informs his mysterious female superior over the radio that he's closing in on Paul, and she recommends using local law enforcement as back-up. Zoil then recruits two inept FBI agents, Haggard (Bill Hader) and O'Reilly (Joe Lo Truglio), to aid in his mission, without telling them the nature of their target.
Graeme, Clive and Paul pull into a motor park run by Ruth Buggs (Kristen Wiig), a creationist Christian, and her controlling father, Moses (John Carroll Lynch). The trio bond around their campgrill and Paul reveals that since he was captured by the government, he had been advising them in all manner of scientific and sociological achievements. Yet Paul had outlived his usefulness as a receptacle of knowledge, and his captors were intending to surgically remove Paul's brain in an attempt to harness his abilities. With help from a friend inside Area 51, Paul sent an S.O.S. to his home planet, and he was escaping to meet up with them. The next morning, Paul inadvertently reveals himself to Ruth, and the trio are forced to kidnap her and make a hasty escape. Paul then shatters Ruth's faith by sharing his knowledge of the universe via telepathic link; at first horrified, Ruth suddenly becomes eager to sin, which her father had raised her to fear doing. She initially doesn't trust Paul, but he heals her eye, as she has been blind in it since the age of four.
Eventually, Paul reveals his intention to return to the girl whose dog he crashed his ship on in 1947 and who subsequently saved his life, who is now an old woman, Tara Walton (Blythe Danner). After spending her life being ridiculed for what she said she saw, Tara seems grateful to see that Paul simply exists. She turns her gas cooker on to make tea, but is interrupted by Haggard and O'Reilly on one side of the house, and Zoil on the other. As the motley crew escapes and drives off with Paul, O'Reilly shoots at them, and the gas ignites, destroying the house. A winded Zoil tries to follow, but Haggard takes off first, running Moses (who'd also been tracking the RV) off the road, and catching up to the RV. However, thanks to an error of judgement, Haggard accidentally drives off a cliff, and is killed, leaving Zoil in hot pursuit. He reassures his superior that he'll have Paul within an hour, but she declares herself tired of waiting, and informs Zoil that she's ordered a military response.
When Paul, Graeme, Clive, Ruth and Tara arrive at the rendezvous, they set off a signal and wait. Eventually, eerie orange lights show up over the surrounding trees, and everyone believes that it is Paul's race. However, it is an army helicopter, with 'the Big Guy' (Sigourney Weaver) on board, Zoil's shadowy superior. As she and three troops move to shoot Paul, Zoil arrives, and it's revealed that he was Paul's inside contact who had helped him to escape. Zoil disarms the men, but is shot in the shoulder. Tara punches out 'the Big Guy', but Moses appears with a shotgun and shoots Graeme dead. Paul heals him and then collapses, exhausted. 'The Big Guy' regains consciousness, but is immediately crushed by the arriving alien ship. Paul begins to depart and informs Tara that she is going with him to live a better life and bids farewell to his friends hoping to meet them again one day.
Two years later, Graeme, Clive, and Ruth are shown again at a comic convention, promoting their new mega-successful comic book, "Paul".