After finishing a concert at Lake Springfield, Green Day tries to engage the audience in a discussion about the environment, but they refuse to listen and throw garbage at them. The pollution in the lake erodes the band's barge, causing them to be drowned. During their memorial, Grampa Simpson has a spiritual experience and frantically prophesies that a disaster will befall Springfield, which only Marge takes seriously. Concerned about the terrible state of the environment, Lisa and her new friend Colin hold a seminar and convince the town to clean up the lake. Meanwhile, Homer and Bart engage in a dare contest, in which Homer dares Bart to skate across town naked. After being caught by the police, Homer allows Bart to take the blame for the dare. At Krusty Burger, Homer adopts a pig to save it from being slaughtered. Marge, identifying the pig as a part of the prophecy, warns Homer to get rid of it, but he refuses and names it Spider-Pig, then renames him Harry Plopper. Homer's fawning over Plopper makes Bart, now fed up with Homer's carelessness, to look to their neighbor, Ned Flanders, as a father figure.

Marge orders Homer to dispose of an overflowing silo full of Plopper's feces. Rather than disposing of it safely at Marge's request, he dumps the silo in the lake, critically polluting it, in order to arrive at the closing Lard Lad Donuts in time to get free donuts. Russ Cargill, head of the Environmental Protection Agency (EPA), informs President Arnold Schwarzenegger of Springfield's pollution crisis and presents him with five solutions. Schwarzenegger then randomly picks the third option – sealing Springfield off from the rest of the world under a giant glass dome.

Being trapped under the dome causes mass hysteria in Springfield and when Homer's silo is discovered on the news, hundreds of townspeople arrive at the Simpsons' house in an attempt to lynch the family. They escape through a sinkhole hidden under Maggie's sandbox, which destroys the house, the debris trapping in the rest of the town. The family is furious at Homer for his blundering, but he convinces them to follow him to Alaska, where he had always planned to go if something like the incident happened. Homer wins a truck by riding a motorcycle around a globe of death and the family restarts their lives in a remote Alaskan cabin.

Meanwhile, as Springfield exhausts its supplies, the townspeople attempt to find another way to escape from the dome. Cargill, mad with power, tricks Schwarzenegger into ordering the town's demolition. The Simpsons see Tom Hanks on television advertising a "new Grand Canyon" on the site of Springfield. Realizing that their hometown is in danger, the family vow to save it, except for Homer, who refuses to partake because of how their friends had turned against them and storms out. When he returns the next morning, he finds his family gone and a videotaped message from Marge explaining that she and their children are returning to Springfield to save it. To prove that her decision is permanent, she tapes her message over their wedding video. An Inuit shaman then helps a distraught Homer to have an epiphany about his selfishness and he vows to save the town. Meanwhile, Marge and the kids are captured by the EPA in Seattle and placed back inside the dome.

The EPA lowers a time bomb suspended by a rope through a hole at the top o…

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The production staff had considered a film adaptation of The Simpsons since early in the series. The show's creator, Matt Groening, felt a feature-length film would allow them to increase the show's scale and animate sequences too complex for the TV series. He intended the film to be made after the show ended, "but that [...] was undone by good ratings". There were attempts to adapt the fourth season episode "Kamp Krusty" into a film, but difficulties were encountered in expanding the episode to feature-length. For a long time, the project was held up. There was difficulty finding a story that was sufficient for a film, and the crew did not have enough time to complete such a project, as they already worked full-time on the show. Groening also expressed a wish to make Simpstasia, a parody of Fantasia; it was never produced, partly because it would have been too difficult to write a feature-length screenplay. At another point, it was briefly suggested to do an anthology-style Treehouse of Horror film, but such suggestion was never pursued. Recurring guest performer Phil Hartman had wished to make a live-action film based on his character Troy McClure; several of the show's staff expressed a desire to help create it, and Josh Weinstein proposed to use the plot of the 1996 episode "A Fish Called Selma" for the film, but the project was canceled following Hartman's death in 1998. The project was officially green-lit by 20th Century Fox in 1997, and Groening and James L. Brooks were set to produce the film.

The voice cast was signed on to do the film in 2001, and work then began on the screenplay. The producers were initially worried that creating a film would have a negative effect on the series, as they did not have enough crew to focus their attention on both projects. As the series progressed, additional writers and animators were hired so that both the show and the film could be produced at the same time. Groening and Brooks invited Mike Scully and Al Jean (who continued to work as showrunner on the television series) to produce the film with them. They then signed series director David Silverman to direct the film. The "strongest possible" writing team was assembled, with many of the writers from the show's early seasons being chosen. David Mirkin, Mike Reiss, George Meyer, John Swartzwelder, and Jon Vitti were selected. Ian Maxtone-Graham and Matt Selman would also join later, and Brooks, Groening, Scully, and Jean also wrote parts of the screenplay. Sam Simon did not return having left the show over creative differences in 1993. Former writer Conan O'Brien expressed interest in working with the Simpsons staff again, although he later joked that "I worry that the Simpsons-writing portion of my brain has been destroyed after 14 years of talking to Lindsay Lohan and that guy from One Tree Hill, so maybe it's all for the best." The same went for director Brad Bird who said he had "entertained fantasies of asking if [he] could work on the movie", but did n…

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Al Jean described the film's message as being "a man should listen to his wife". In addition, the film parodies two major contemporary issues, religion and environmentalism. The theme of environmentalism is present throughout the film: in Homer's polluting of Lake Springfield, Green Day's cameo, Lisa's activism and her romance with Colin. The villainous Russ Cargill is head of the Environmental Protection Agency. Reviewer Ed Gonzalez argued the plot was a satire of the government's reaction to the effects of Hurricane Katrina on New Orleans. Ian Nathan of Empire magazine criticized this focus, believing it gave the film an "overt political agenda [which] border[s] on polemic". James D. Bloom of Muhlenberg College commented on the "explicitness" of the film's "intellectual agenda", on this issue, shown particularly through Lisa. He wrote that the film's first post-opening credits scene, which sees Green Day fail in an attempt to engage their audience on the issue of the environment, "sets in motion a plot expressly built around cultural agenda-setting" and "reflection on timely 'issues'."

Religion is focused on in Grampa's momentary possession, and Marge believing what he said to be a message from God. Groening joked the film "posit[s] the existence of a very active God", when asked if he believed it was likely to offend. Mark I. Pinsky, author of The Gospel According to The Simpsons, said the film "treats genuine faith with respect, while keeping a sharp eye out for religious pretension and hypocrisy of all kinds". Regarding the scene where the tenants of Moe's Tavern and the Church switch locations, he believed it took the "chance to unmask everyone's human fallibility." In analyzing the role of Ned Flanders, he wrote, "It is [the] willingness of The Simpsons to depict all the different sides of us [...] that makes it so rich and funny on our complicated relationship with religion." Trees are a motif in the film, and they were implemented in every important or emotional scene throughout the film. The animators inserted an apple tree behind Lisa and Colin during their initial meeting, which was a reference to the biblical figures of Adam and Eve and the Garden of Eden.