Walter, a puppet, and his human brother Gary have been fans of the Muppets since their youth, and as adults, continue to live together in Smalltown. Gary plans a vacation to Los Angeles to celebrate his tenth anniversary with his girlfriend, Mary, inviting Walter to accompany the two so they can visit the Muppet Theater. However, upon the three arriving at the Muppet Theater, they find it in ruins, discovering that Statler and Waldorf are selling the theater to Tex Richman, an oil magnate, who intends to destroy the Muppet Studio to drill for oil. Waldorf explains that the Muppets have a certain amount of days to raise 10 million dollars to reclaim the theater.
Walter, Gary and Mary arrive at the mansion of Kermit the Frog and explain the situation to him. Though Kermit is distressed, he realizes that the only way to earn 10 million dollars is to put on a show, which the Muppets have not done in years. Nevertheless, they manage to reunite the Muppets, though Miss Piggy, who is now an editor in chief, refuses to rejoin the group, forcing them to replace her with Miss Poogy, a Moopet, impersonators of the Muppets. The Muppets are rejected by several TV networks until an executive, Veronica, agrees to give the Muppets a 2-hour opening in her network's schedule due to the sudden cancellation of one of their hit shows, but on the condition that the Muppets recruit a celebrity guest.
The Muppets repair the theater, but the rehearsal does not go well, and they fail to find a celebrity guest. However, Miss Piggy returns and kicks Miss Poogy out, and Kermit request that Walter join them to find his talent. Kermit then requests that Tex return the studio, but he refuses, revealing that they will lose their rights to the Muppet name, which will be given to the Moopets, who have allied with Tex. In desperation, the Muppets abduct Jack Black to be their sponsor. Mary returns to Smalltown after Gary forgets their anniversary dinner, leading to a falling out between him and Walter. Afterwards, Gary returns to Smalltown and reconciles with Mary while Walter accepts himself as a Muppet.
The Muppet's telethon goes well with celebrity support from Black, but Tex cuts the power to the telethon. However, Gary and Mary return to Los Angeles and manage to repair it. Walter finds his talent by whistling, receiving acclaim from the audience. However, Tex destroys the telephone pole, damaging the tote board. A glitch in the tote board is discovered when Fozzie bangs his head on the board, revealing that the Muppets hadn't received enough donations. Kermit states that the Muppets tried, which is what matters, and they plan to start over. Upon exiting the theater, the Muppets discover a large gathering of fans and press, and Walter joins the Muppets with encouragement from Walter. Tex receives a head injury and thus returns the Muppet Theater to the Muppets while Gary proposes to Mary, who accepts.
- Jason Segel as Gary.
- Amy Adams as Mary.
- Chris Cooper as Tex Richman.
- Rashida Jones as Veronica.
- Steve Whitmire as Kermit/Beaker/Statler/Rizzo/Link Hogthrob/The Newsman.
- Eric Jacobson as Miss Piggy/Fozzie Bear/Animal/Sam Eagle/Marvin Suggs.
- Dave Goelz as Gonzo/Dr. Bunsen Honeydew/Zoot/Beauregard/Waldorf/Kermit Moopet.
- Bill Barretta as Swedish Chef/Rowlf/Dr. Teeth/Pepe the Prawn/Bobo/Foozie Bear/Whatnot Farmer/Muppet Gary.
- David Rudman as Scooter/Janice/Miss Poogy/Wayne.
- Matt Vogel as Floyd Pepper/Camilla/Sweetums/80's Robot/Lew Zealand/Uncle Deadly/Rowlf Moopet/Crazy Harry.
- Peter Linz as Walter.
- Alan Arkin as Muppet Studios Tour Guide.
- Bill Cobbs as Grandfather.
- Zach Galifianakis as Hobo Joe.
- Ken Jeong as Punch Teacher host.