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Immediately following the events of their last film, the Muppets find themselves at a loss as to what to do for their sequel until Dominic Badguy (Ricky Gervais) suggests they go on a European tour with him as their tour manager.

As the Muppets begin their tour, the criminal mastermind Constantine, a near-exact double for Kermit the Frog in appearance, escapes from a Siberian Gulag and joins his subordinate Dominic to begin a plot to steal the UK Crown Jewels. Once the Muppets arrive in Berlin, Dominic secures them a show at a prestigious venue. Kermit, frustrated with the group's incessant requests and Miss Piggy's insistence they marry, goes for a walk at Dominic's suggestion. Constantine ambushes him and glues a fake mole onto his cheek, matching Constantine's own, then slips away. Mistaken for Costantine, Kermit is arrested and sent to the Gulag. Taking Kermit's place, Constantine's blunders in imitating him are covered by Dominic; however, Animal knows the truth. Constantine and Dominic steal paintings from a museum while the Muppets perform. The next morning, Interpol agent Jean Pierre Napoleon (Ty Burrell) and CIA agent Sam Eagle grudgingly team up to apprehend the culprit whom Napoleon believes to be his nemesis "The Lemur" - the number-two criminal in the world.

Meanwhile, Kermit has attempted several times to escape the Gulag, but is thwarted each time by prison guard Nadya (Tina Fey); knowing of his true identity, Nadya is obsessed with him as Miss Piggy. Nadya orders Kermit to help organize the prisoners' annual talent show.

Following hidden instructions on the stolen painting, Constantine and Dominic divert the tour to Madrid. Constantine allows the Muppets to perform whatever they wish, much to Walter's confusion. During this show, Constantine and Dominic break into a museum and destroy a roomful of busts to find a key needed for their plan. Even though the performance is a disaster, the Muppets receive critical acclaim. Sam and Napoleon deduce the connection between the crimes is the Muppet tour, and the pair interrogate the Muppets, only to find they're too ill-equipped to be guilty. The instructions on the stolen key lead Constantine and Dominic to schedule the next show in Dublin, Ireland.

In Dublin, Walter discovers Dominic has been bribing critics to ensure a packed house and rave reviews, while Fozzie Bear notices Kermit's resemblance to Constantine; they realize the truth. Constantine attacks Walter and Fozzie, but Animal fends him off and the three escape from the train so they can rescue Kermit. During the Dublin performance, Dominic steals a locket from a museum and Constantine proposes to Miss Piggy onstage; Piggy accepts, and the pair plan a ceremony to be held at the Tower of London, where the Crown Jewels are kept.

Fozzie, Walter, and Animal reach the Gulag on the night of the performance, and Kermit uses it as a front to allow them, himself, and all the prisoners to escape. The four Muppets infiltrate the Tower as the wedding begins, and Dominic (with the help of Bobby Benson's Baby Band) uses the stolen key and locket to disable the security system protecting the jewels and steals them.

Kermit interrupts the ceremony, revealing Constantine's ruse, but the crook takes Piggy hostage and flees to a helicopter. He is intercepted by Dominic - actually the Lemur - who intends to double-cross him. Constantine ejects him from the helicopter and tries to take off with Piggy, but Kermit jumps aboard and the rest of the Muppets climb atop each other to stop the escape. Kermit and Piggy knock out Constantine and both criminals are arrested. Nadya arrives in London to arrest Kermit for escaping. The Muppets tell her if she arrests him, she will have to take all of them as well. She relents, allowing Kermit to go free. The Muppets perform at the Gulag with the prisoners participating.