The game follows the Simpson family and their friend Apu Nahasapeemapetilon as they witness many strange incidents that occur in Springfield; security cameras, mysterious vans, crop circles, and a "new and improved" flavor of the popular soft drink Buzz Cola that causes insanity.

Taking matters into their own hands, they discover numerous shocking secrets, and soon realize these incidents are part of a larger alien conspiracy, caused by Kang and Kodos.

The gameplay largely focuses on exploration and missions; players often race enemies and interact with supporting characters on timed quests.

Production was extensive, as the team sought to differentiate the game from Road Rage, deeming that their new entry in the franchise required a different direction.

[2] In the week leading up to Halloween, mysterious happenings are occurring in Springfield; a horde of robot wasps descend upon the city, a "new and improved" brand of Buzz Cola is launched by television personality Krusty the Clown and introduced to store shelves, and black vans begin appearing around town.

Lisa eventually finds Bart on a ship in Springfield harbor, albeit with memory loss and mumbling unintelligibly while occasionally mentioning the sedans and cola.

After helping Snake Jailbird with his community service, Apu learns that the cola trucks are registered to the Springfield Museum of Natural History.

Apu and Bart learn that the wasp cameras are filming the antics of Springfield for Kang and Kodos' struggling intergalactic reality show, Foolish Earthlings.

After Homer gathers supplies to protect his family and home from the marauding zombies, he decides to pursue an alien probe vehicle to the Springfield Nuclear Power Plant.

[6] The developer, Radical Entertainment, received the rights to create games for The Simpsons franchise when they demonstrated a playable prototype.

[8] Lead programmer Cary Brisebois considered the GameCube version the hardest to develop, with its 24MB of RAM necessitating tricks such as loading animations into audio memory.

[7] A port for the PlayStation Portable entered development, but never released due to return on investment, as by then the voice actors had renegotiated their contracts to increase their fees.

The player is able to enter some of them, including the Kwik-E-Mart, Moe's Tavern, Springfield Elementary School, and The Android's Dungeon and Baseball Card Shop.

All character voices were supplied by the actual cast, and the series' writers wrote the entire story for the game, including dialogue, with a total of 12,231 recorded lines.

"[8] The game's soundtrack was primarily composed by Marc Baril, with additional compositions by Jeff Tymoschuk and Allan Levy.

[10] The soundtrack includes various arrangements of the original Simpsons theme by Danny Elfman, and features specific melodies for each playable character; for example, Bart's gameplay is accompanied by hard rock, while Lisa has laid-back motifs that Steven Hopper of GameZone compared to beach party films.

[7] Praise focused on the move from the Simpsons television series to the video game format, while criticism targeted some aspects of gameplay.

[49] Entertainment magazine Variety surmised that Hit & Run was the first Simpsons game to include humor comparable to what was in the television series.

[50] Hit & Run's parodical take on the Grand Theft Auto III video game was praised by several reviewers.

Zach Meston of GameSpy considered it to "deftly satirize Grand Theft Auto while being almost as entertaining", and suggested that Hit & Run improved several gameplay aspects that it borrowed from Grand Theft Auto, including instant mission restarts, a superior guidance system, and an easily accessible collection of vehicles.

[3] The combination of the Simpsons universe with the gameplay of the Grand Theft Auto series was also praised by Douglass C. Perry of IGN as "pure brilliance".

Nick Catucci of The Village Voice gave the Xbox version a score of nine out of ten and stated, "This delightful, deep, and detailed (but unfortunately not cartoon-style cel-shaded) rip on the Grand Theft Auto series critiques itself better than any untenured academic could.