Best friends Graeme Willy and Clive Gollings are British comic book and sci-fi enthusiasts who travel to the United States to attend the annual San Diego Comic-Con. Clive is trying to write his own sci-fi book, and Graeme is illustrating Clive's book. In addition to going to the convention, they embark on a road trip through the Southwestern U.S. to visit UFO sites on a remote desert highway at night.
After a brush with homophobic rednecks at a diner, they watch a car driving erratically and crashing. Stopping to offer assistance to the driver, he is revealed to be Paul, an alien. Graeme agrees to give him a ride, despite Clive fainting and wetting his pants upon seeing him.
Later, Special Agent Zoil of the Secret Service arrives at the car-crash site, informing his unseen female superior, known as "the Big Guy," that he is closing in on Paul. She sends rookies Haggard and O'Reilly to assist. Clive remains paranoid over Paul's intentions, considering his appearance as evidence of a conspiracy. Then Paul explains the government fed his image to the public to keep them from panicking if anyone encounters his race.
Graeme, Clive, and Paul later camp at an RV park run by Christian fundamentalists, one-eyed Ruth Buggs and her father Moses. The next day, when Ruth sees Paul, she faints, so they take her with them. During an argument, Paul convinces Ruth to question her beliefs and uses his healing power to cure her blind eye.
Stopping at a bar, Ruth calls her father, but Zoil intercepts the call. She is accosted by the rednecks and a bar fight ensues. They escape when Paul terrifies them into fainting. Later, at another RV park, Ruth is questioned by Agent Zoil, but plays dumb and escapes. Meanwhile, Haggard and O'Reilly have figured out about Paul. Confronting Zoil, he orders them to return to base, but they go behind his back and try to catch the alien on their own.
The group soon arrives at Tara's, who rescued Paul when he crashed on Earth 60 years ago, accidentally killing her dog (hence Paul's name) in the crash (opening scene). As no-one believed her story, she has spent her life as a pariah. Although angry at first, she forgives Paul and prepares to make tea for her visitors. Haggard, O'Reilly and Zoil arrive and surround the house. The group flee but O'Reilly shoots at them, igniting gas from Tara's stove and destroying her house with him inside. Haggard pursues and catches up to the RV but loses control and drives off a cliff. Zoil reassures the Big Guy that he will have Paul within the hour but tired of waiting, she orders a "military response".
Paul, Graeme, Clive, Ruth and Tara arrive at Devils Tower National Monument, where they set off fireworks to signal Paul's mothership. A helicopter suddenly arrives with agents and the Big Guy. Zoil appears and initiates a stand-off, unexpectedly shooting the agents, before being wounded. He is revealed to be Paul's friend, attempting to aid his escape under the guise of capturing him. During the fight, Tara knocks out the Big Guy. Moses arrives unexpectedly and fires at Paul, but hits Graeme instead. Paul once again uses his healing powers, reviving Graeme in spite of the danger to himself, causing Moses to believe Paul to be a messiah.
Graeme and Ruth admit their feelings for each other and kiss, but the Big Guy regains consciousness and holds the group at gunpoint. Just as she is about to kill them, she is crushed by the landing transport ship. Paul says goodbye to his friends and offers Tara a chance to go with him, promising to give her a new life after ruining her childhood and accidentally killing her dog. The aliens go home as the remaining humans wave. Two years later, Graeme, Clive and Ruth are at another Comic-Con, where Graeme and Clive are promoting their new bestselling novel titled Paul.
Simon Pegg as Graeme Willy
Nick Frost as Clive Gollings
Seth Rogen as Paul (voice and motion capture)
Jason Bateman as Special Agent Lorenzo Zoil.
Kristen Wiig as Ruth Buggs
Bill Hader as Agent Haggard
Blythe Danner as Tara Walton
Mia Stallard as Young Tara Walton
Joe Lo Truglio as Agent O'Reilly
John Carroll Lynch as Moses Buggs, Ruth's father
Jane Lynch as Pat Stevens
David Koechner as Gus, a redneck whom Graeme and Clive first encounter in a Nevada gas station.
Jesse Plemons as Jake, Gus's friend.
Sigourney Weaver as "The Big Guy". In an interview with Graham Norton, Weaver stated: "It's a love letter to sci-fi fans. I jumped at the chance to be in it. To find a comedy that also pays homage to sci-fi is a dream come true."
Syd Masters as himself, singing cowboy on stage
Jeffrey Tambor as Adam Shadowchild, a famous science fiction writer
Steven Spielberg as himself (voice)