The story begins in the Forbidden City in 1887, where Chon Lin (Fann Wong) shares tea with her father, the Keeper of the Imperial Seal. She informs him about her brother, Chon Wang (Jackie Chan), who is thriving as a sheriff in Carson City, Nevada. However, her father coldly dismisses her brother, declaring him dead to him. This tense moment escalates when Lord Nelson Rathbone (Aidan Gillen) leads a fierce group of Boxers into the citadel, attacking the Keeper, who is fatally wounded after Rathbone steals the seal. Before he dies, he entrusts a puzzle box and a letter meant for Wang to Lin.
Meanwhile, in the Wild West, Chon Wang is proving himself as an effective sheriff, proudly having apprehended numerous fugitives. His deputy spends time engrossed in a book titled Roy O'Bannon Vs. The Mummy, an exaggerated tale depicting Wang as nothing more than a cowardly sidekick. Wang soon receives a package containing the puzzle box and Lin's letter, which reveals the tragic news of their father's death and her quest to track down the murderer in London.
Determined, Wang heads to New York City to seek his former partner Roy O'Bannon (Owen Wilson), needing his share of their previous spoils to afford a ticket. Roy has since abandoned law enforcement, ended his romance with Falling Leaves, and squandered their fortune on a failed investment in a Zeppelin. Now working as a hotel waiter and part-time gigolo, their attempts at prostitution to fund their journey lead to an encounter with the Mayor of New York, who is searching for his daughters, one of Roy's recent clients. In a chaotic brawl, Wang defends them against a crowd of New York police and they manage to stow away to London in a shipping crate. During their journey, Wang confides in Roy about their father's demise, prompting Roy to pledge his support in reclaiming the seal.
Upon their arrival, Rathbone fabricates a tale of unrest in China, spectacularly presenting a Bengal Tiger to the Queen, which shocks the British Parliament. In their quest, Wang and Roy find themselves victims of pickpockets, including a street-savvy boy named Charlie (Aaron Johnson), who steals their belongings. They engage in a chaotic chase and are subsequently captured by the police. Inspector Artie Doyle (Thomas Fisher) recognizes their heroics against a local gang and returns Roy's watch, stolen by Charlie. He reveals that Lin has been apprehended for attempting to murder Rathbone, gaining the moniker "Looney Lin". Infatuated with their exploits, Doyle is excited to meet the real Roy O'Bannon, though Roy's attempts to secure Lin's release fail miserably.
As Rathbone plots his next moves, Wu Chow (Donnie Yen) infiltrates his carriage, revealing a deadly alliance, and provides Rathbone with the dagger that ended the life of the Keeper. Later, as Wang and Roy navigate the streets of London, they are drawn into a nobleman's house by Charlie, who points out an invitation to an extravagant gala at the castle.
Donning disguises—Roy as the mock "Major General Sherlock Holmes" and Wang as the "Maharaja of Nevada"—they infiltrate a private library where they find Rathbone. Unfortunately, he slips away into a secret passage, which Wang discovers hidden within a fireplace. While Roy amusingly entertains himself with a copy of the Kama Sutra, Wang discovers treasures from the British Empire in the secret room. In a twist of fate, Lin rescues Roy and Wang from Rathbone's guards, but the nefarious Lord soon sets the building ablaze. During the chaos, Charlie grabs the seal, while Lin escapes and Wang and Roy commandeer an anachronistic vehicle for an absurd getaway that ends with a crash into Stonehenge.
As the dust settles and Roy regains consciousness from the crash, his imagination leads him to a steamy fantasy involving Lin. However, upon discovering a drunken revelry among prostitutes that Wang orchestrated, she is heartbroken. Their troubles intensify as they find themselves ensnared by Rathbone and his Boxers. Bound and helpless at a pier, the trio confronts Wu Chow, who reveals a sinister plot involving the seal and the royal family.
After a daring escape, Wang, Roy, and Doyle employ Doyle's astute observations to track the stolen seal back to Madame Tussauds wax museum, where they reclaim it, but soon find themselves arrested again. Surprisingly, Charlie reveals his full name to be Charlie Chaplin in a humorous nod to history, and he helps break them out just in time for the Jubilee Ball, where the royal family will be present.
In a climactic showdown, Wang faces Wu Chow once more, while Roy confronts Rathbone atop the iconic Big Ben. With a fierce sword fight ensuing, Roy's quick reflexes save him from falling, and Wang channels his grief and anger into defeating Rathbone. The daring duo descends by clinging to a British flag, landing right in front of Queen Victoria, who graciously knights them alongside Doyle.
With new titles, Roy expresses his ambition to launch into the world of films, playfully suggesting they venture into Hollywood, which ignites a spark of excitement about their future. As they ride away with their newfound ally, Charlie, Wang opens the puzzle box, uncovering a heartfelt message from his father about the significance of family, uniting their adventures in an unforgettable quest across time and culture.
