The film commences with Ralph Wiggum enthusiastically singing along to the iconic 20th Century Fox logo. We then transition to a fictional film within the movie, Itchy & Scratchy: The Movie, which opens in a cosmic setting on the moon. In this tale, Itchy eliminates Scratchy, subsequently returning to Earth where the media hails him as a hero. Not long afterward, Itchy ascends to the presidency. While in the White House, he sees what he believes to be the deceased Scratchy waving a sign stating, “I’m telling,” which sends President Itchy into a panic. In a fit of rage, he retaliates by launching a hundred missiles at Scratchy, a scene witnessed by the reluctant audience at a movie theater, including the Simpsons.
Homer, feeling disengaged, jumps to his feet and exclaims, “Boring!” to which Lisa responds, “Dad, we can’t see the movie!” This ignites Homer's humorous rant lamenting why they are shelling out money to view something that is typically aired on television, dubbing the audience—a bunch of “gigantic suckers.” This leads into an incredibly stylish rendition of the classic Simpsons opening theme.
After the credits roll, we find Green Day hosting a concert at Lake Springfield, where they perform the Simpsons theme song. Their post-performance dialogue about environmental issues incites fury from the crowd, who retaliate by tossing trash into the lake, subsequently causing their barge to dissolve and sink, resulting in their demise. The following day, during a brief memorial service at church, Grampa is overtaken by divine inspiration, forewarning the residents of an impending catastrophe. Responding to this ominous message, Marge is determined to decipher its true meaning.
Simultaneously, Lisa passionately advocates for environmental preservation, yet struggles to garner support. She eventually encounters Colin, an Irish boy who shares her ecological concerns. Meanwhile, Homer receives a chore list from Marge, one of which involves addressing a growing sinkhole. Instead of tackling it responsibly, he cleverly conceals it under Maggie’s sandbox. When another chore requires him to repair the roof, Homer and Bart engage in a daring contest, with Homer challenging Bart to ascend the antenna. As Bart gets stuck, Homer shakes it to bring him down. A new dare tasks Bart to skate at Krusty Burger while unclothed. Initially balking at the idea, Bart reluctantly agrees after being threatened with being branded a coward.
After a series of misadventures, Bart finds himself temporarily detained while Homer comically shows up with socks and a shirt, completely omitting pants. Ned Flanders, ever the helpful neighbor, comes to Bart's rescue by offering him a pair of pants, prompting a budding friendship grounded in mutual understanding. Meanwhile, Krusty is filming a commercial which, after completion, turns dark when he orders the pig used in the shoot to be slaughtered. The terrified pig rushes to Homer, who adopts it and affectionately names it Spider-Pig.
That evening, Lisa organizes a conference titled “An Irritating Truth,” focusing on the alarming pollution levels threatening the town’s lake. In response, Mayor Quimby declares a state of emergency to initiate protective measures. As part of these efforts, a barrier is put in place around the lake to prevent further contamination, humorously proven foolproof when Cletus attempts to dispose of a possum.
As fate would have it, Marge soon questions Homer about the waste produced by Spider-Pig, after discovering a silo overflowing with refuse. In a response filled with well-meaning but misguided logic, Homer admits to aiding in the overflow, shocking Marge and motivating her to insist on proper waste disposal. While waiting at the landfill, Homer learns about free donuts being given away after Lard Lad Donuts shut down. In his eagerness, he takes a shortcut by dumping the silo’s contents into the lake, resulting in severe pollution and grotesque mutations among the local wildlife.
In a critical meeting at the White House, Russ Cargill, head of the EPA, shows President Arnold Schwarzenegger a mutated squirrel as evidence of Springfield's dire situation and presents five drastic action plans to tackle it. Opting for a random choice, the President unwittingly enables the construction of a giant dome over Springfield to contain the city’s pollution.
As the story unfolds, Maggie accidentally falls through a neighboring sinkhole, ending up outside the dome, before returning home. When the police expose Homer’s role in polluting the lake, an angry mob descends upon the Simpson residence, ultimately leading to its fiery demise. Forced to flee through the expanding sinkhole, the family finds refuge in a crumbling motel, where Homer reveals a secret escape plan: relocating the family to Alaska, a proposition that Marge reluctantly accepts.
The following day, the family visits a carnival where Homer participates in an exhilarating challenge called the “Ball of Death” and, in winning a truck, catalyzes their move. While attempting to adapt to life in Alaska, Springfield's residents plot to demolish the dome. Russ Cargill proposes new solutions to the President, who again randomly selects a plan that spells disaster for Springfield.
Amidst all the chaos, Homer discovers a heartfelt message from Marge urging him to save Springfield at all costs, leading to a frantic chase across icy terrain after Marge and the kids are captured by the EPA. Guided by a celestial vision of the Boob Lady, Homer embarks on a desperate mission to reunite with his family.
Adventurous mishaps culminate as Homer faces off with Cargill in a climactic moment, leading to a series of events where Bart heroically assists his father in saving Springfield. They ultimately disable the bomb threatening the town, resulting in the dome's destruction and the community's revival.
In the end, Springfield begins to reestablish itself, and the Simpson family moves forward, echoing the often-chaotic, comedic tone fans love. The film concludes delightfully with references to potential sequels and quirky post-credit scenes that leave audiences eagerly anticipating more adventures.
