Bart Simpson goes to a video game store and buys a new ultra-violent Grand Theft Scratchy game, which is promptly confiscated by his mother Marge. Suddenly, a video game manual lands right in front of him. Miraculously, after having read the manual, the members of the Simpsons family discover that each of them possesses a unique superpower. Toying with these, however, attracts the attention of the aliens Kang and Kodos, who decide to invade the Earth. Now the unlikely superheroes must not only protect the town of Springfield from an alien assault, but also find the true reason behind their newly acquired powers, and perhaps their very existence.

The Simpsons Game is a 3D action game with platforming and light puzzle-solving elements, based on the long-running cartoon. The game is divided into sixteen episodes, each containing cutscenes reminiscent of the original Simpsons TV series. Every episode is set in a different environment; some of the scenarios are based in Springfield, while others take the player into meta-virtual worlds. Some of the episodes parody a popular game or genre, having names like Medal of Homer or Neverquest. Each stage features two members of the Simpson clan working together to achieve the goal. Players must switch back and forth using each family members' unique powers to complete the level. Most of the game's versions allow two-player cooperative play.

The four controllable characters have their own unique abilities, which are used for combat, puzzle-solving, or exploration-related purposes. Homer can expand into a rolling blob or inflate himself with helium and float for a while; later, he learns a few other transformation abilities. Bart can become Bartman, using a grappling hook to access certain areas, as well as move upwards in air streams with his cape. Lisa's main ability is called "Hand of Buddha", which is used mainly for moving around large objects; she can also play her saxophone to stun or confuse enemies. Finally, Marge can gather people with her megaphone and control their actions, as well as send the little Maggie into crawlspaces only she can access. Some of these abilities have limited uses and must be either recharged or replenished with special items, while others are available only at specific trigger points.

The PS3 and Xbox 360 versions also contain free-roaming gameplay - exclusively in those versions player characters can leave the Simpsons' house between missions and freely wander through virtual Springfield. Familiar landmarks (such as Moe's Tavern, etc.) are present and can be explored as well. These locations may contain additional dialogue and events. It is possible to use the bus to travel quickly to various destinations.