Brothers Walter and Gary, residents of Smalltown, are fans of the Muppets, having watched The Muppet Show throughout their youth. Now adults, Gary plans a vacation to Los Angeles with his girlfriend, Mary, to celebrate their tenth anniversary, inviting Walter so he can tour the Muppet Studios. Mary is okay with Walter coming, as she is a Muppet fan as well, but feels Gary's devotion to Walter is distracting from their relationship.
In L.A., the three visit the neglected and rundown Muppet Studios. During the tour, Walter sneaks into Kermit's office; he overhears Statler and Waldorf selling the Muppet Theater to oil magnate Tex Richman and his henchmen Bobo the Bear and Uncle Deadly. After Statler and Waldorf leave, Walter overhears Richman reveal his plan to destroy the theater and drill for oil. A hysterical Walter barely tells this to Gary and Mary, but remembers that Statler and Waldorf added that if the Muppets can raise $10 million by the time their original contract expires, they can repurchase the theater.
Agreeing to stop Richman, they find Kermit at his mansion and inform him of Richman's plot. Kermit realizes he must organize a telethon to raise the money, which appears difficult since the Muppets have gone their separate ways over the course of the past several years. Convinced to try, Kermit sets off with the three to reunite the group. Kermit successfully dissuades Fozzie from continuing to perform in Reno, Nevada with the Moopets, a tribute group of uncouth Muppet impersonators. Meanwhile, Gonzo has become a plumbing magnate and, despite his initial objection, destroys his business and joins them. Animal is recovered from a celebrity anger-management clinic, before being instructed by his sponsor Jack Black to keep away from drums. The other primary Muppets rejoin through a montage. Later in Paris, the group finds Miss Piggy working as an editor for "plus-sized" fashion at Vogue Paris, but they fail to convince Miss Piggy to return, so the group replaces her with her Moopet counterpart Miss Poogy.
The Muppets return to Los Angeles and rebuild the theater. They pitch their telethon idea to several television networks, but are rejected. Following a show's cancellation, CDE executive Veronica gives the Muppets the newly-vacated two-hour slot in the network's schedule, on the condition that they find a celebrity host. Miss Piggy soon returns and forces Miss Poogy out, but informs Kermit that she still refuses to work with him and instead chooses Pepe as her dance partner. Later, the Muppets' first rehearsal is wildly unsuccessful and Kermit is unable to contact a celebrity. Needing enough acts to fill the two-hour slot, Kermit attempts to inspire Walter to find a talent and perform in the telethon. Meanwhile, Mary goes sightseeing alone, as Gary has devoted all his attention to his brother and the Muppets, forgetting their anniversary.
A desperate Kermit, still unable to find a celebrity host with 12 hours to go before the contract expires at midnight, implores Richman to return their studio to them. Richman refuses and reveals he plans to give the Muppets' trademark names, which he will also acquire at the time the contract expires, to the Moopets. Kermit gives up and returns to his mansion. Miss Piggy then enlists the remaining Muppets to kidnap Black as the celebrity host. Meanwhile, after discovering a devastated Mary has returned to Smalltown, Gary realizes that he must repair his relationship with Mary and follows her back home to reconcile, leaving Walter alone. The Muppets convince Kermit to keep trying now that they have a host. The telethon begins and gradually attracts a large audience, with the Muppets raising donations via telephone pledges, with support from celebrity callers and a kidnapped Black serving unwillingly as host. During the show, Richman cuts the theater's power supply, but Gary and Mary, having returned to L.A., restore the power. A furious Richman then attempts to destroy the theater's television transmitter, but Uncle Deadly, regretful of his complicity in Richman's plot, throws him off the roof. Kermit and Miss Piggy finally reconcile and the Muppets perform "Rainbow Connection" as their final act.
During the credits, Gary proposes to Mary, Richman returns the theater and naming rights to the Muppets after Gonzo accidentally gives him a head injury, and Kermit and Miss Piggy enjoy their private life.
