Gary and Walter are brothers and best friends. From birth, Walter was always different from Gary and the other boys his age. He was always shorter than the others, and is made of felt. One day Walter discovered "The Muppet Show" - a 1970's variety show headlined by Kermit the Frog and the Muppets. Gary instantly became a fan of the Muppets and dreamt that one day he would visit Muppet Studios and meet Kermit the Frog. As time wore on, his dream never faded.
Gary (Jason Segel) is now a grown man. His ten-years steady girlfriend Mary (Amy Adams) and he are planning a two-week romantic getaway to Los Angeles. Walter excitedly tells Gary to visit the Muppet Studios and to send him a postcard. Gary refuses saying that he won't send a postcard since Walter is coming too! Walter excitedly packs his bags while Gary goes to meet Mary. Mary is an elementary school teacher, teaching advanced automotive mechanics to 8 year olds. Gary bursts into her classroom just as the bell rings. Mary bids farewell to her students and tells them to enjoy their two-week spring break. Gary produces a bouquet of yellow flowers, which he accidentally crushed inside his jacket. She takes the flowers anyway and excitedly tells Gary what she wants to do in Los Angeles. Gary mentions that Walter is coming along too, which dampens Mary's spirits. She day-dreams that she is in Paris and Gary proposes to her in front of the Eiffel Tower.
Gary, Mary and Walter sing about their excitement as they leave "Small Town USA" on a Greyhound bus headed for Los Angeles. When they arrive they immediately go to Muppet Studios, the venue for the Muppet Show, which also has a back lot tour and rides. To everybody's surprise the studios are in horrible shape. A surly tour guide (Alan Arkin), takes them around the dilapidated park and when no one is looking, Walter sneaks into Kermit the Frog's empty office. Inside Walter sees dusty relics of the Muppet Show including Kermit's tuxedo. He hears voices coming from the office adjacent and hides beneath a desk. Tex Richman (Chris Cooper) enters the room and is accompanied by his two assistants/henchmen: Bobo the Bear and Uncle Deadly. They're followed shortly after by Statler and Waldorf. Statler and Waldorf hold the deed to the Muppet Studios and Richman intends to purchase it so he can "turn it into a museum." The pair of old Muppets tell Richman that the only way the sale could be nullified is if the Muppets can raise the $10 Million needed to buy back the Studios by Friday at midnight. After Statler and Waldorf leave Richman divulges his true plan. The Studio is seated directly above a massive oil reserve, and he intends to tear down the Muppet Studios to get it. Walter overhears the evil plan and runs from the studio, screaming all the way back to his hotel room. He tells Gary and Mary about Richman's plan, and they decide that they must find Kermit the Frog.
The three drive up to Bel Air where they find a palatial estate with Kermit and Miss Piggy's faces on the front gate. With some prodding, Walter convinces Gary to throw him over the gate's electrified fence. Walter flies into the fence and is horribly electrified. A dark figure appears behind them signaled by the harmony of a gospel choir - Kermit. Kermit invites them all in to treat the injured Walter. Inside they explain Richman's plan to Kermit and that the only way to save the studio is to have a fund-raising telethon to gather the $10 Million to buy back the studio. Through some soul-searching, Kermit agrees. The four, along with Kermit's chauffeur 80's Robot, set off to Reno to find Fonzie the Bear. Fonzie is doing his best to capitalize on the Muppet's once-famous name. He's a lounge singer at a third-rate casino - he sings with a surly bunch of Muppets knockoffs (named Moopets) including Miss Poogy on vocals and Dave Grohl as "Animool" on drums. Fonzie is quickly convinced to go with them.
Next they all visit Gonzo, who over the last twenty years has formed a multi-million dollar plumbing supply company in the Rust Belt. Gonzo dismisses his former friends, saying that his life as CEO makes him too busy to be a Muppet again. As they leave, Walter tells Gonzo that his Daredevil acts were one of his favorite parts of the Muppet Show. Outside they're all surprised as Gonzo, with his chicken secretary, appears on top of the factory. He peels off his suit revealing his famous daredevil costume, which he claims to have worn under his suit and tie every day for the past twenty years, and leaps from the building onto the ground below. He agrees to be a part of the telethon and bids his plumbing job goodbye by blowing up the building.
Next, the group drives to a behavioral clinic for celebrities where they find Animal being treated for anger issues. His sponsor Jack Black, played by Jack Black, is also being treated for anger issues. Jack Black explains that Animal's outbursts are all triggered by the "D word" - Drums. Soon after, a massive melee breaks out and amidst the chaos Animal is freed and the group leaves. A montage follows in which all of the former muppets, save for Miss Piggy, are found and invited to be a part of the telethon. The Muppets drive to France (using the speedy method of "Map" Travel) to find Miss Piggy. Miss Piggy is a successful clothing designer with a very full schedule. The Muppets are initially dismissed by her secretary (Emily Blunt), but after forming themselves into a "Muppet Man" with an appointment, they gain access to her office. Miss Piggy turns down the offer to be a part of the telethon, saying that she would rather spend her time in Paris than be a Muppet again. Distraught, the group heads back to Los Angeles and pick up a replacement for Miss Piggy, Miss Poogy, and head to every major network to pitch The Muppet Telethon. All of the channels, including Univision, turn the Muppets down. They finally end up in TV executive Veronica's (Rashida Jones) office. Veronica explains that on a scale of popularity, the Muppets are non-existent, and that children nowadays are only interested in shows like "Punch Teacher" - a TV game show hosted by Ken Jeong which revolves around students answering questions and punching their teachers for points. As she is about to dismiss the Muppets from her office, a junior programmer (Donald Glover) rushes into her office saying that they have to yank Punch Teacher off the air because they're getting sued by the Teachers Association of America. Veronica is now left with a massive two hour gap in her schedule two days from now. She agrees to give the time-slot to the Muppets.
The Muppets, Gary, Mary, and Walter head to the Muppet Studios and immediately get to work returning it to its former glory. Over the next two days Walter grows closer to the Muppets and further apart from Gary. They clean the dusty theater, repair broken floorboards and lightbulbs, and make it like new. Miss Piggy arrives, telling Kermit that her heart is with the Muppets and swiftly kicks Miss Poogy out of her dressing room. On the eve of the Telethon Mary sulks, wishing that Gary would spend more time with her and less time with Walter and the Muppets; after all, this trip was supposed to be just for the two of them. She goes out to eat by herself, goes to museums by herself, and is a solo tourist. That evening Gary returns to the hotel room with a bouquet of intact yellow flowers, having finally found time to dedicate to her. She asks him what he has planned for dinner, to which he replies "I dunno. What do you want to do?" This infuriates Mary, as today is their ten year anniversary, and she storms out. Gary visits Walter and soon realizes his error in mistreating Mary and runs back to his hotel room where he finds a hand written note from her. She's gone back to Small Town USA without him.
It is the day of the telethon and even though the theater is clean, the show is in shambles. Veronica is threatening to pull the show's plug and air Webster reruns instead. Walter is anxious because Kermit expects him to display some talent in the show, but he has none. To make matters worse there is no celebrity to headline the telethon. Kermit puts the Muppets in charge of finding one. They arrive at a film set and knock on a trailer door. Jack Black opens the door, dressed in a ping-pong MoCap suit, and is immediately attacked by the ninja-clad Muppets and thrown into the trunk of their car. With six hours to go Tex Richman is convinced that the Muppets will not raise the money and that the theater is as good as his. To make matters worse Richman reveals to Kermit that at midnight not only will he gain ownership of the Studio, but the Muppets' names and likenesses as well. He brings in Fonzie's "Moopets" - all twisted, bizarro versions of the actual Muppets and explains that at midnight the Moopets will become the Muppets. To make matters worse, Gary, through some soul-searching, decides that he is a man and not a Muppet and jumps on a Greyhound back to Small Town USA. He knocks on Mary's door and apologizes for forgetting about her in Los Angeles. Meanwhile, Walter realizes that he is a Muppet and not a man (his human form portrayed by Jim Parsons) and accepts that he must have a hidden talent he can use in the show.
The show begins, the theater doors open and save for "Hobo Joe" (Zach Galifianakis) there are no audience members. A large tickering, LED board, which represents the money donated so far, reads $0 through the first act. Gary and Mary watch the show on a TV while they eat. Mary regrets convincing Gary to leave and the two decide to return to the theater by map. After a rocky start, families across the country slowly start tuning in and donating money to save the Muppet Studios. Jack Black awakens backstage, finding himself tied up and dressed in a tuxedo. He's brought out on stage, but his pleas of kidnapping only make the audience laugh. In one act, Gonzo prepares to lob a bowling ball at Jack Black, but Gonzo's shoulder dislocates, causing the bowling ball, and his arm, to continually spin with no sign of stopping, sparing Jack's life. In a Barbershop Quartet number, in which Jack Black plays the customer, the Muppets accidentally shrink his head due to overuse of hot towels. The audience eats it up, pushing the donations north of $2 million. Backstage more celebrities including Whoopi Goldberg, Neil Patrick Harris and Judd Hirsch appear to man the phones.
Just outside Tex Richman and his cronies take a fire axe to the building's main circuit, cutting the power to the building. Gary and Mary arrive, and manage to restore the power with a little over an hour to go in the show.
Walter's act is next, and he nervously makes his way to the stage. After a lengthy introduction by Kermit, Walter screams horribly and runs backstage, cutting his act short. Animal, who to this point has avoided playing his drums for fear of becoming angry again, finally accepts his drum sticks and returns to the drums mid-show.
On top of the studio Richman plans to climb the building's main TV antenna and sever it with a pair of bolt cutters. Uncle Deadly, finally fed up with Richman's evil ways, wrestles the bolt cutters away from Richman, causing him to fall from the antenna onto the roof.
Kermit and Miss Piggy, finally reconciled, sing a moving rendition of Rainbow Connection, with accompaniment by drummer Animal, which pushes the donations total north of $9.5 million. With 5 minutes left in the show, Kermit realizes that he's run out of ideas, and that the last few minutes of the show will be dead air. They'll never make the last half million. Walter steps up with a talent to fill the time, having composed himself, and after the commercial break, he steps on stage. Walter displays his operatic whistling talent which moves the audience and brings the total to $9,999,999. Outside a severely disheveled Richman steals Kermit's car and uses it to ram the building's telephone line tower. Inside the phones go dead just as the clock strikes midnight, leaving the Muppets $1 short of their goal. Richman enters the theater and mocks the Muppets, teasing them as failures who fell short at the very last second. Fonzie defiantly punches the LED ticker, hoping that the last dollar might appear after a solid hit. To everybody's surprise the board changes, not to $10 Million, but rather $99,999.99 - the board wasn't displaying the decimal point. The Muppets fell well short of their $10 Million goal. Richman giggles evilly and orders that the no-longer Muppets (as he now owns their names and likeness) leave his building. The dozens of saddened Muppets, along with Gary and Mary, slowly file out of the theater and onto Hollywood Blvd were they find a gigantic crowd of thousands of Muppet fans, all holding hand-made signs singing their praises. Richman follows and shouts angrily at the Muppets and their fans. Gonzo, his bowling-ball arm still freely spinning in the socket, lets loose the ball, and accidentally hits Richman, knocking him to the ground. The Muppets continue to celebrate in the streets with their thousands of adoring fans. Gary gets down on one knee. In front of everybody, he proposes to May, who eagerly accepts.
In the prologue, it is revealed that Richman's demeanor has changed, probably due to getting hit in the head with a bowling ball, and he is now a Muppet fan and will neither tear down the studio nor take their identities. The entire cast, human and Muppet, breaks into a stirring rendition of Mah Nà Mah Nà.
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