In the game's manual, Saliva is erroneously referred to as Billy's dog. Within the context of the show, Saliva is owned by Mandy.

Billy and Mandy's alternate Robot costumes, and the addition of Horror's Hand originate from the 2007 made-for-TV movie "Billy & Mandy's Big Boogey Adventure". The game released in September 2006, with the film premiering in March 2007, so the addition of these aspects could serve as early promotion.

The final boss of the game, the Brain-Eating Meteor, originates from the season 1 episode "Little Rock of Horrors". The character's musical sequence from the episode, the Aurelio Voltaire Hernández song "BRAINS!", is also featured as the fight's background music. Despite this, the game does not credit Hernández or the song's other co-writers, Gregor Kitzis, Matthew Goeke, and George Grant. Hernández also goes uncredited in the game's cast list despite his vocals from the original episode being retained in-game.

The lack of credit for "BRAINS!" reflects a longstanding issue with the song since its original commissioning, in which Cartoon Network repeatedly failed to properly attribute it to Hernández, instead crediting it to the show itself when airing the sequence as a music video. According to Hernández, the initial failure to credit him resulted in Cartoon Network revealing that it was under no legal obligation to do so, per the terms of Hernández's contract, before eventually pulling the music video from circulation. Hernández stated that he was aware at the time that he would be signing away the song's rights, but did not know until then that the network reserved the right to opt out of attribution. Despite the dispute, Hernández remained friends with series creator Maxwell Atoms and later contributed another song, "Land of the Dead", to the TV film Billy & Mandy's Big Boogie Adventure.

The unlockable character Mogar, the rockstar alter ego of Billy's dad Harold, originates from the season 2 episode "Battle of the Bands".

According to series creator Maxwell Atoms, the decision to make the game a fighting game was due to the characters constantly being in conflict with one another in the original TV show. The game Power Stone inspired the developers to specifically make it a 4-player arena fighter.

In an early version of the console release, Billy's Backyard (the final stage of story mode) had 2 players fighting. This could imply that the game originally had co-op support for story mode or that the stage would have been playable in versus mode.