Trama

The Simpson family learn they are part of a video game and are given superpowers to save their 8-bit predecessors.

The game opens in Homer's dream about the land of chocolate, but is interrupted as Bart asks him for money to buy the latest video game "Grand Theft Scratchy". After acquiring a copy of the game and then having it confiscated by Marge almost immediately, Bart comes upon the instruction manual from "The Simpsons Game". Reading through the manual, he discovers that he and the rest of his family members have special powers; Bart uses his "Bartman" powers to stop Jimbo Jones, Kearney and Dolph from stealing from the Natural History Museum, Homer uses his ability to become a huge ball to win an eating contest, Lisa uses her powers of meditation to stop a deforestation project, and Marge with her powers to influence crowds to stop the release of "Grand Theft Scratchy" in Springfield.

At home, as everyone talks about how they love their powers (but then argue over it because of the problems their powers have caused all over Springfield), Kang and Kodos launch an alien attack upon Springfield. Among their havoc-inducing strategies include bringing a giant Lard Lad statue to life and turning all the dolphins evil. Even Sideshow Bob forms an alliance with them. Realizing none of their powers are strong enough to defeat the aliens, Bart and Lisa visit Professor Frink who presently is in the "Game Engine", a factory-like realm where video games are made. Frink gives them "The Simpsons Game" player's guide to better understand how to use their powers as well as gain new ones, and the Simpsons family rally again to stop the alien invasion.

In order to find out the truth, the family turns to the Internet to discover more about the powers they have in the game, but are accidentally sent back to the game engine when Homer spills beer while trying to play solitaire. There, they discover Will Wright destroying copies of the (fictional) game The Simpsons: Escape from Krusty Island, purely on the basis that the game is dated and no one is playing it anymore. The family manages to save their 8-bit predecessors, who tell them that as they too are just characters in a video game, they are also doomed to become obsolete when the next "Simpsons" game comes out, and that the only way to prevent this is to talk to "The Creator" himself.

To get to The Creator, the Simpsons collect four key cards in four separate "Simpsons" video games currently in development. In "NeverQuest", Marge and Homer become characters in a fantasy video game and must defeat the two-headed dragon Selmatty. In "Big Super Happy Fun Fun Game", Homer and Lisa meet Mr. Sparkle, who tells them they must fight through Comic Book Guy sumo wrestlers and defeat three separate monsters: Ratachu (Jimbo), Turdle (Ralph), and Dirty Donkey (Terri/Sherri), so that Mr. Sparkle can get the keycard from Mr. Dirt (Milhouse). In "Medal of Homer" Homer and Bart must first collect the white flags of surrender from a town in France, and then get the French paintings back from Private Burns (Mr. Burns) on his aircraft carrier, the S.S. Real Crazy, to obtain the third key card. In "Grand Theft Scratchy," Marge has to gather a mob of blue dogs to rebuild sleazy businesses into more wholesome entertainment outlets while fighting off Itchys and Scratchys with Lisa, and then defeating Poochie and collect the final key card.

When the family returns, they have a brief debate with the 8-bit Simpsons about how older video games worked. They then proceed to meet The Creator, who turns out to be Matt Groening. Groening refuses to help the family, and escapes after distracting the family with copies of Bender and Dr. Zoidberg from Futurama. Returning to Springfield, the family realizes they have one last resort, God himself, they go to Heaven and when there, must fend off people they've defeated before, as well as both William Shakespeare and Benjamin Franklin. After discovering and beating God in a godlike version of Dance Dance Revolution, God promises to restore Springfield when Bart threatens to destroy his memory card containing his Oblivion saved game. Then they discover that He is actually playing a giant video game, of which "The Simpsons Game" was just a mini-game. Before the Simpsons depart, Lisa asks God if He ever considered Himself as part of a video game - the game then is shown with Ralph Wiggum playing it, and Ralph then breaks the fourth wall by tapping on the screen and calling to his father that people are watching him.