A golden retriever eagerly scratches at the front door of the farm house, begging to get out. A little girl, Tara, walks downstairs. She lovingly refers to the dog by name, "Paul", and lets him out. Paul the dog scampers across the front yard, stops, and looks straight up. A UFO appears out of nowhere, and flattens the dog, as Tara watches.
Cut to the present day, Graeme Willy (Simon Pegg) and Clive Gollings (Nick Frost), two english comic fans, attend the San Diego Comic Con. They peruse the showbooths, buy souvenirs, and meet scifi personalities. They excitedly wait to meet science fiction author Adam Shadowchild (Jeffrey Tambor). Clive reveals to Adam that he too is a sci-fi author, and produces a manuscript of his latest novel, complete with a colorful illustration of a buxom, green alien woman, drawn by Graeme. Adam refuses to read the manuscript for legal reasons but commends Graeme on the artwork - "Three tits! Awesome!"
Graeme and Clive return to their hotel, where they're briefly mistaken by room service to be boyfriends. Clive calls the motor home rental agency, and learns that their RV is sitting outside in the parking lot. The two explain how they plan on taking a UFO-history roadtrip from San Diego all the way to Roswell.
In the morning, the two take off in the motor home, stopping at numerous UFO fanatic photo-spots along the way, including the black mailbox and a UFO-themed diner where they're waited on by country waitress Pat Stevenson (Jane Lynch.) Half way through their meal a pair of surly hunters, Gus and Jake (David Koechner and Jesse Plemons) enter the restaurant and tease the two Englishmen, calling them gay. Graeme and Clive, fearing a "Deliverance" scenario, flee the restaurant in the RV, accidentally crashing into Gus and Jake's SUV along the way. Graeme and Clive head for the highway, constantly checking their rear view mirror for Gus and Jake's truck - a pair of headlights appears behind them, along with a honking horn. Frightened, Graeme floors the RV, but they're soon overtaken. They look at the car, seeing that it is not Jake's truck, but a black Crown Victoria. Relieved, Graeme lets off the gas, moments before the Crown Vic loses control, flips, and rolls to a stop at the side of the road. Graeme and Clive exit the RV, and search the crash site for survivors. They find the Crown Vic empty. A dark silhouette, smoking a cigarette, appears behind them. The tiny figure walks into the light, showing himself to be an alien. Clive faints and pees his pants, Graeme looks on in horror. Graeme and the alien, who calls himself Paul (Voiced by Seth Rogen), load Clive's unconscious body into the RV. Graeme nervously converses with Paul, who surprisingly speaks perfect english and knows plenty of pop culture references.
Another Crown Vic pulls in behind the destroyed car at the side of the highway. Special Agent Lorenzo Zoil (Jason Bateman) surveys the crash site, sees a puddle of Clive's urine, and phones his boss (Sigourney Weaver) and tells her that the alien escaped in another car, probably with help. "The Big Guy" tells Agent Zoil to rendezvous with a pair of junior agents a few miles away. Agent Haggard (Bill Hader) and Agent O'Reilly (Joe Lo Truglio) get the call, and are ordered to set up a roadblock on the highway near their position, but are told nothing about Paul.
Clive awakens after fainting, and upon not seeing Paul in the RV, he supposes that both he and Graeme hallucinated the encounter. Paul appears out of thin air, demonstrating an ability to camouflage his skin by holding his breath. The two freak out, and moments later a bird slams into the RV's windshield. They pull over, and examine the bird's body. Paul picks up the dead bird, and using a special alien ability, he revives the bird - and then eats it. They jump back into the RV and drive down the road, but are stopped moments later by Haggard and O'Reilly at the roadblock. Paul camouflages himself while the two agents search the RV. O'Reilly makes note of Clive's urine soaked pants drying on a clothesline. The pair, finding no evidence, let Graeme and Clive go, but not before looking at their book's manuscript and cover art, remarking "Three tits! Awesome!"
On the road, Graeme slowly warms up to Paul, and sketches him in a sketchbook. Clive on the other hand, distances himself from the Paul. As they travel, Paul reveals the impact that he's had on popular culture. He tells a story of a telephone conversation he had with Steven Spielberg in 1980 where he suggested that E.T. should be able to heal with the power of touch (like Paul). Moreso he claims to have invented Agent Mulder, and been responsible for the stereotypical alien design prominent in pop culture. While heading North, the three stop at a rural convenience store to stock up on snacks and gas. As they come to a stop, a highway patrolman pulls in next to them. Clive and Graeme quickly pay for their food and flee for fear of being arrested for harboring a fugitive. Zoil arrives at Haggard and O'Reilly's roadblock, finding them playing hide and seek instead of searching cars. They claim to have only seen two cars: a pair of hunters in an SUV and two english nerds in a motor home; one with a small bladder. Zoil makes the connection and the three head after the RV.
The three spot a trailer park off the highway, turn off, and park for the night. At the trailer park, they meet an odd, eye-patched girl named Ruth (Kristen Wiig) who co-manages the trailer park. Graeme instantly falls for her. She takes Clive's passport (a requirement for renting the parking spot for the night) while Paul manages to hide from her gaze. That night the three party - dancing, singing, eating hot dogs, and telling stories. Paul explains to the pair that he was a scientist from his planet, but due to his poor piloting skills, he was captured by the US government 60 years earlier. He managed to escape, contact his race, and will be picked up at a certain time and place somewhere north of their position. Ruth, curious to see what they're up to catches a glimpse of Paul, before getting called back into the manager's office by her father, Moses (John Carroll Lynch). The next morning Graeme, Clive, and Paul awake to hear somebody pounding on the RV's door. It's Ruth looking to collect the three's $25 rental fee. While there, Ruth questions where the third member of their party is (Paul) after having seen a bit of him the night before. Paul, hiding in the bathroom, feigns stomach troubles. Ruth asks the three about religion, and preaches her personal, creationist beliefs while deriding evolution as a myth. Paul, still hiding in the bathroom, argues with Ruth's naive beliefs and finally reveals himself to her, causing her to faint in the RV. Frightened, Graeme, Clive, and Paul get ready to flee the trailer park with Ruth, still passed out in the RV. Fearing that the police track them down using Clive's passport, Paul disguises himself, sneaks into the main office, and searches for the passport. He manages to find it, but not before Moses appears, toting a shotgun. Paul flees the building, avoiding numerous shotgun blasts from Moses, and the three manage to get away, leaving Graeme's sketch of Paul flipping the bird captioned with a giant "Fuck You". Moses gathers up the sketch and phones the police.
Zoil arrives, with Haggard and O'Reilly in tow. Zoil interrogates Moses, who pleads for the safe return of his daughter. He hands over an old elementary school photo of Ruth (complete with eye patch). Haggard, while searching the office happens across the sketch of Paul and secretly pockets it.
Back in the RV Ruth is coming to. Paul apologizes for scaring her, while Graeme and Clive apologize for kidnapping her. Ruth, incensed, demands to be let off the bus. Paul, eager to gain her trust, asks Ruth about her bad eye, which is revealed to be pigment-less and white. Paul cups his hands over her eye and absorbs the disease into his own body, and later dispels it. Ruth is shocked to have two good eyes, and while thankful to Paul, refuses to believe he is an Alien, but is rather a demon. Paul, frustrated, grabs hold of Ruth - the duo's minds instantly intertwine and, as Paul explains, all of his knowledge is transferred into Ruth's brain. Ruth, tired and confused, pleads to get off the bus. Torn between faith and science, Ruth argues with Graeme, and ultimately accepts that her sheltered life no longer makes sense. Feeling absolved of sinful guilt Ruth lets free a torrent of kindergarten obscenities whilst grabbing hold of Graeme's crotch, and ultimately forgives the trio. Inside Paul asks Clive why he's been acting so oddly around him. Clive confesses that he always wanted to meet an alien, but didn't expect that he would pee his pants and faint when he did. The two make up.
The foursome continues north, and stops at a restaurant/bar along the way. In the rowdy Cantina, Ruth calls her father's phone and is surprised to hear Special Agent Zoil's voice on the other end. She talks about Paul walking around with his "spaceman balls" which sends O'Reilly into a laughing fit. She nervously hangs up but not before her location is transmitted to Zoil, Haggard, and O'Reilly. To make matters worse Moses, Gus and Jake arrive, and a bar-brawl breaks out. The three manage to escape the restaurant, with Gus and Jake on their tails. As they're about to be caught Paul appears in the RV door exclaiming "It's probing time!" Gus and Jake faint, and the four take off, with Moses following closely behind. Zoil, Haggard, and O'Reilly arrive shortly thereafter. Haggard shows the sketch of Paul to the hysteric Gus and Jake who upon seeing it burst into tears. Haggard's suspicion of their mission, and why they don't know anything about it, grows.
The four pull off at another secluded rest stop. Over night they camp out by a fire where Paul and Ruth share a powerful joint rumored to have killed Bob Dylan (who Paul claims to be dead). Ruth and Graeme's nearly kiss in front of a Western-wear boutique window, before being interrupted by Paul. In the morning Graeme, Clive and Paul awake to find Ruth gone and a note written on Graeme's forehead - "Went to sleep in the RV." The trio begins to head back to the RV park, but are shocked to find a busy street dividing them and the RV. Paul claims that he won't be able to hold his breath long enough to remain camouflaged - this gives Graeme an idea. Moments later the three appear, walking down the street, with Paul dressed as a little cowboy, an outfit seen earlier on a mannequin in the boutique's window. They soon lose Clive, who is distracted by a sword perched in the comic book shop's window. He tells Graeme to go get the RV while he and Paul wait in the comic shop. Unbeknownst to the trio Zoil arrives at the RV park, and begins searching for Paul. He comes to their RV, knocks on the door, which is answered by Ruth, who he does not notice without her eye patch. In town Agents Haggard and O'Reilly look for anything suspicious. O'Reilly, himself a big sci-fi fan, walks into the comic book shop, where he sees Paul, who poses as though he were a rubber puppet. O'Reilly, still fascinated by the thought of "Spaceman balls" unzips Paul's zipper and feels around, causing Paul to break his silence and curse him out. Crying, he calls for Haggard, who arrives to find Clive dressed in an Alien mask. The RV pulls up out front, Clive and Paul jump inside, while avoiding gunfire from the two agents. Haggard and O'Reilly, now convinced that they've seen an Alien, confront Zoil who tells them to shut up and return to HQ.
Graeme, Clive, Paul and Ruth continue to head north. Paul explains that he'll need a signal to attract his rescue ship. They drive to a nearby firework store, and shoplift the biggest/most expensive firework available and flee. Zoil's radio crackles. "The Big Guy" tells him that two english nerds matching the perps' description were just caught shoplifting fireworks. Zoil spins around and pursues them. Soon the foursome is forced to repel Zoil, Haggard, O'Reilly and Moses. They turn off the main road and hide behind a billboard until they're out of danger. They continue north, per Paul's instructions and arrive at the old farm house from the beginning of the film. Paul explains how he wishes to apologize to the little girl whose dog he killed 60 years earlier, when he landed his ship on it. The little girl, Tara, now an old woman answers the door (Blythe Danner) and reluctantly invites them all in. She recounts to Paul the day she first met him, how she pulled him out of the ship, and saved his life, before the G-men came and hauled him away. She was tormented for the rest of her life and now lives as a lonely hermit. She goes to the kitchen to prepare tea for them all, turns on the gas range, and is surprised as a tear-gas grenade crashes through her window. Outside Zoil, Haggard, and O'Reilly are all closing in on the farmhouse. Graeme, Clive, Paul, Ruth and Tara flee the house as O'Reilly crashes his way in. O'Reilly spots the five running to the RV. He smashes out a kitchen window and fires a single shot, which ignites the stove's gas. The house explodes, killing O'Reilly.
The five take off in the RV. Haggard follows in Zoil's Crown Vic, and Moses catches up in his old beater pick-up truck. Haggard shoots Moses in the chest and runs his truck off the road. He soon catches up to the RV, being driven by Paul, and is about to shoot him when he drives his car off a cliff, and dies. Zoil rallies his strength, takes O'Reilly's Crown Vic and follows the five. He calls "The Big Guy" who tells him that she's had enough of his ineptitude and that she will be coming to take care of Paul herself. The five near their destination, which appears over the horizon - Devil's Tower. They arrive, and set off their massive firework-signal. Zoil sees the signal, and quickly assembles an automatic rifle. The five wait for the mothership, and are surprised to see two giant yellow lights cresting over the tree-line, which ends up being a helicopter. The helicopter lands, and off steps "The Big Guy" (again, Sigourney Weaver) dressed in a cocktail dress, flanked by three armed soldiers. To make matters worse Zoil appears behind the group, with his gun pointed at them. He fires, not at them, but at The Big Guy's armed guards. It is revealed that Zoil helped Paul escape and has been trying to help him all along. The Big Guy, without her guards fist-fights with Graeme and Clive and is ultimately knocked-out cold by Tara. Moses arrives shortly thereafter, holding his life-saving bible, with a bullet in it, and shoots at the group, mortally injuring Graeme. Moses is promptly disarmed, and the group mourns Graeme's death. Paul claps his hands together and places his hands on Graeme's chest, absorbing the gunshot wound and regaining life to Graeme, who awakens. Paul lays, apparently dead, but awakens a moment later, fully healed. The five, along with Zoil and Moses, are happy to see Paul alive and in one piece. The Big Guy appears behind them, with a snub-nosed revolver pointed their direction. She nearly pulls the trigger when WHAM, Paul's rescue ship appears out of nowhere, and flattens The Big Guy.
The group says it's goodbyes. Paul offers Tara the chance to come with him, which she accepts. Clive passes his manuscript to Paul, who having read it, gives it a so-so review and makes a few recommendations for the future. Paul passes the manuscript to an Alien ship-mate who, upon seeing the cover exclaims, "Three tits! Awesome!" The ship slowly takes off while Paul says a few final goodbyes, and finally rockets out of the atmosphere.
Two Years Later: Graeme and Clive, who are once again at Comic Con, are now celebrities for having written the wildly successful comic book "Paul." They're introduced on stage by Adam Shadowchild while Ruth and Pat Stevenson cheer them on.
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