In Springfield, as rock band Green Day perform on Lake Springfield, the band members fail to engage the audience in a discussion about the environment. They are killed when the pollution in the lake erodes their barge, causing it to sink. At their memorial, Grampa Simpson frantically prophesies the destruction of the town but only Marge takes it seriously. Lisa and her new friend Colin, whom she has fallen in love with, hold a seminar where they convince the town to clean up the lake. Meanwhile, Homer adopts a pig from Krusty Burger, which causes his jealous son Bart (who is now fed up with his father's carelessness) to look to their neighbor, Ned Flanders, as a father figure.
Homer stores the pig's feces in an overflowing silo, which disgusts Marge. Homer attempts to dispose of it safely at Marge's request, but gets distracted and instead dumps the silo in the lake, critically polluting it. Moments later, a squirrel jumps into the lake and becomes severely mutated. Flanders and Bart discover the squirrel during a hike, and the EPA captures it. Russ Cargill, head of the EPA, informs President Arnold Schwarzenegger on Springfield's pollution crisis and presents five countering options. The President randomly picks the action of enclosing Springfield in a giant glass dome. When Homer's silo is discovered, an angry mob of townspeople ransack the Simpsons' home. The family escapes through a sinkhole in Maggie's sandbox and flee to Alaska. Homer wins a motorcycle contest and is awarded a truck, which the family use to restart their life.
After three months of failed escape attempts, cracks start to appear in the dome and Cargill, not wanting news of what he has done to become international, plots to destroy Springfield. In Alaska, the Simpsons see an advertisement featuring Tom Hanks for a new Grand Canyon on the site of Springfield. Horrified that their hometown is in danger, Marge and the kids decide to save it, but Homer objects to helping the people who tried to kill them. The family abandon Homer but are captured by the EPA and placed back in the dome. After an encounter with a mysterious Inuit shaman, Homer has an epiphany that he must save the town in order to save himself.
Homer learns his family are in Springfield and a helicopter lowers a time bomb suspended by rope through a hole in the roof of the dome. Homer climbs to the peak of the dome using superglue and descends the rope, knocking the escaping townspeople and the bomb off. After reuniting with Bart, they use a motorcycle to travel up the side of the dome and Bart throws the bomb through the hole, seconds before detonation. The bomb explodes, shattering the dome. Cargill attempts to kill Homer and Bart for thwarting his plan, but Maggie knocks him out with a boulder. The townspeople praise Homer, who rides off with Marge on the motorcycle into the sunset as Springfield begins restoration.
Dan Castellaneta - Homer Simpson, Abe Simpson, Krusty the Clown, Groundskeeper Willie, Mayor Quimby, Sideshow Mel, Mr. Teeny, EPA Official, Itchy, Barney Gumble, Stage Manager, Blue Haired Lawyer, Multi-Eyed Squirrel, Hans Moleman, Panicky Man, Kissing Cop, Bear, Boy on Phone, NSA Worker, Officer, Rich Texan, Santa's Little Helper, Squeaky-Voiced Teen
Julie Kavner - Marge Simpson, Selma Bouvier, Patty Bouvier
Nancy Cartwright - Bart Simpson, Maggie Simpson, Ralph Wiggum, Todd Flanders, Nelson Muntz, TV Daughter, Woman on Phone, Kearney Zzyzwicz
Yeardley Smith - Lisa Simpson
Hank Azaria - Moe Szyslak, Chief Wiggum, Cletus Spuckler, Professor Frink, Apu Nahasapeemapetilon, Lou, Comic Book Guy, Captain McCallister, Bumblebee Man, Dr. Nick Carl, Male EPA Worker, Dome Depot Announcer, Kissing Cop, Carnival Barker, Gas Station Clerk, Drederick Tatum, EPA Passenger, Robot, Wiseguy
Harry Shearer - Mr. Burns, Smithers, Ned Flanders, Reverend Lovejoy, Lenny, President Arnold Schwarzenegger, Seymour Skinner, Kent Brockman, Dr. Hibbert, Otto Mann, Scratchy, Skull, Toll Booth Operator, Guard
Pamela Hayden - Milhouse Van Houten, Rod Flanders, Jimbo Jones
Tress MacNeille - Medicine Woman, Agnes Skinner, Crazy Cat Lady, Colin, Cookie Kwan, Sweet Old Lady, Mrs. Muntz, Plopper, Female EPA Worker, Lindsey Neagle, GPS Voice, TV Son, Girl on Phone, Dolph Starbeam
Albert Brooks - Russ Cargill
Karl Wiedergott - EPA Officer, Man
Marcia Wallace - Edna Krabappel (scenes deleted)
Russi Taylor - Martin Prince
Maggie Roswell - Helen Lovejoy, Miss Hoover
Phil Rosenthal - TV Dad
Joe Mantegna - Fat Tony
Green Day - Themselves
Tom Hanks - Himself
also known as The Simpsons or The Simpsons Movie: Yellow Harvest in the working title
based on the popular long-running Fox animated television series The Simpsons (1989–present)