The film is a film-within-a-film, wherein Kermit the Frog, the rest of the Muppets and gang create havoc in a screening room, where they are about to watch The Irelanders' Massive Adventures of The Muppet Movie. When asked by Robin if the film depicts how the Muppets began, Kermit responds "It's sort of approximately how it happened."
As the story opens, Kermit is enjoying a relaxing afternoon in a Florida swamp, singing a tune (the Oscar-nominated "Rainbow Connection") and strumming his banjo, when he is approached by an agent named Bernie (Dom DeLuise) who recognizes his talents and encourages Kermit to pursue a career in Hollywood. Inspired by the idea of "making millions of people happy," Kermit sets off on a cross-country trip to Hollywood, initially via bicycle but eventually via Studebaker after teaming with Fozzie Bear, who had been working as a hapless stand-up comedian in a sleazy bar, whose owner and pianist are cameoed by James Coburn and Paul Williams respectively. During their journey, they are pursued by the villainous Doc Hopper (Charles Durning, speaking with a Southern accent and wearing an outfit similar to Colonel Sanders), owner of a struggling French-fried frog legs restaurant franchise, and his shy assistant, Max (Austin Pendleton). Doc Hopper wants Kermit to be the new spokesman for his restaurants, but when Kermit refuses, Hopper refuses to accept "No" for an answer and resorts to increasingly threatening means of persuasion.
Kermit and Fozzie's journey also includes misadventures which introduce them to a variety of eccentric characters, some played by human guest stars, others played by Muppets. During one of their drives, they encounter Big Bird and offer him a ride. Big Bird declines stating that he's heading to New York City to make a debut in public television. Kermit and Fozzie Bear encounter Dr. Teeth and The Electric Mayhem and their manager Scooter who plan to turn an abandoned church into a coffee house. They manage to disguise Kermit's car so that Doc Hopper can't recognize them. They end up encountering Gonzo and Camilla the Chicken whom had been working as plumbers until their truck crashes into Kermit and Fozzie's car. When it comes to getting a replacement car from a used car dealer owner Mad Man Mooney (Milton Berle), they meet Sweetums and invite him to join them. Sweetums runs off and Kermit drives away unbeknownst that Sweetums has left to pack his things. At a carnival, the group meets Miss Piggy following a beauty contest (she falls in love with Kermit in the process). She joins Kermit and Fozzie as they continue traveling to Hollywood. Sweetums is still trailing Kermit. At a local motel, Kermit meets up with Rowlf (who works as a pianist at a lounge). Doc Hopper and Max kidnap Miss Piggy and Doc sends a call to Kermit to exit the motel where Kermit runs into Doc's henchmen because Doc Hopper said that if Kermit didn't, Miss Piggy would be slaughtered. Doc Hopper has hired a mad scientist named Professor Max Krassman (Mel Brooks) in an attempt to brainwash Kermit. Fortunately, the scientist insults Miss Piggy just before he starts the process, causing her to break free in a rage and defeat Doc Hopper's henchmen. Immediately after freeing Kermit, Miss Piggy gets a call from her agent about a job and leaves Kermit to attend it.
Following a problem with the film, the movie continues as Kermit's group is now joined by Rowlf. Meanwhile, Doc Hopper goes to an even further scheme by hiring an assassin named Snake Walker (Scott Walker) who kills frogs for a living. Doc Hopper broadcasts on the CB Radio threatening for Kermit to surrender and agree to Doc Hopper's deal or he will become a frog burger. When night falls, Kermit's car breaks down leaving the group stranded in the desert. Luckily for Kermit, the Electric Mayhem and Scooter arrive in their bus having followed the script that Kermit left behind and end up taking them to Hollywood.
The next day, Max appears to Kermit disguised as a motorcycle policeman to warn Kermit that Doc Hopper has hired an assassin to kill Kermit. Refusing to be hunted any longer, Kermit attempts a Western-style showdown in a ghost town where the group meets Dr. Bunsen Honeydew and his assistant Beaker (who owns a laboratory in a ghost town). Kermit breaks tradition by trying to talk Hopper into backing off, but Hopper refuses and orders his henchmen to kill him and all his friends. Kermit is saved only when one of Dr. Bunsen's inventions, "insta-grow" pills, temporarily turn Animal into a giant who is able to permanently scare off Hopper and his men.
The Muppets and gang proceed to Hollywood, where they finally meet the imposing producer and studio executive Lew Lord (Orson Welles) (a reference to Lord Lew Grade who in real life gives The Muppet Show the green light), and hires them on the spot under "the standard rich-and-famous contract" after Kermit reveals why they've come. The film ends with Kermit and the gang attempting to make their first movie, which turns out to be a surreal pastiche of their experiences, hinting that the movie they're making is the same one the audience has been watching all along, but a huge stage accident occurs causing most of the props to collapse and fall, and cause the lights to explode. 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After the end title appears, Sweetums tears through the screen "finally" having caught up with the others to the amusement of the audience who then talk amongst each other as the credits roll. After the credits finish rolling, Animal tells the viewers to go home, then he says goodbye and passes out.