In 2009, best friends Graeme Willy and Clive Gollings—played by Simon Pegg and Nick Frost—embark on an exciting adventure to attend the annual Comic-Con convention in San Diego, California. After the convention, they decide to hit the road, traveling in a rented RV to explore various sites of significant extraterrestrial interest scattered throughout the southwestern United States.
Their journey takes a quirky turn in Arizona at the Little A'Le'Inn, where they unwittingly encounter two hunters who mistakenly assume their relationship to be romantic. In a rush to escape the awkward situation, Clive accidentally backs their RV into the hunters' truck, leaving a noticeable dent.
As night falls, Graeme and Clive notice headlights tailing them, and believing it to be the hunters, they hastily flee in their RV. To their relief, the vehicle that catches up is merely a passing car. However, the situation escalates when the car crashes right in front of them, prompting a fateful investigation by the duo, where they stumble upon an alien named Paul, voiced by Seth Rogen, who is in urgent need of assistance.
Initially shocked by Paul's arrival, Graeme consents to give him a lift, much to Clive's displeasure. Meanwhile, a dubious government agent named Lorenzo Zoil (portrayed by Jason Bateman) arrives, intent on capturing Paul. He communicates with an unknown female superior, suggesting he may unleash local law enforcement for backup, and along the way, he enlists two clumsy FBI agents, Haggard (Bill Hader) and O'Reilly (Joe Lo Truglio), without revealing the true nature of their mission.
Graeme, Clive, and Paul make a stop at a motor park owned by Ruth Buggs (Kristen Wiig), a devout creationist, and her oppressive father, Moses (John Carroll Lynch). Things quickly heat up as the trio bonds over a campfire grill, with Paul revealing his past existence with the government. He shares that he had advised them on various scientific matters and even contributed to pop culture, like inspiring Steven Spielberg's E.T. and creating the fictional character Fox Mulder. Unfortunately, his tenure is coming to an end as the government plans to use him for experimentation.
In a surprising twist, Paul helps Ruth overcome her long-standing disability by healing her blind eye and thus shatters her beliefs, sparking a newfound desire to explore life's darker side. Meanwhile, Zoil and the agents are hot on their trail, and things take an unexpected turn as the hunters confront the group yet again.
Things escalate in a small town when O'Reilly unexpectedly sees Paul in a comic book store, which sends everyone scurrying away from the inevitable confrontation. Tensions reach a boiling point as Zoil tries to follow suit, dishing out orders, only to find his own agents turning against him.
Eventually, Paul's journey leads him back to an old friend, Tara Walton (Blythe Danner), who had once saved him decades ago. Yet, much to their dismay, they are ambushed by Zoil and his team at her house. In a climactic scene filled with chaos, Paul heals Graeme after Moses inflicts a fatal blow, showcasing the consequences of his powers as he collapses from exhaustion.
After a suspense-filled showdown, and with characters left shaken by the harrowing experiences, Paul ultimately departs in a spaceship, offering Tara a chance at a new life. Two years later, Graeme, Clive, and Ruth are seen at another comic convention, showcasing their successful comic adaptation about their extraordinary adventure, while O'Reilly miraculously survives the earlier explosion, hinting that their story will continue.
