Is the direct sequel to Yu-Gi-Oh! The Sacred Cards (2002), but whereas that game was a direct adaptation of the Battle City arc of the anime and manga, this game is an original story and takes place in an alternate continuity from the anime, featuring game-exclusive villain Reshef the Dark Being, who doesn't exist in the anime or manga.
Reshef the Dark Being, a villain and card who was exclusive to this game, was eventually printed as a real card in the Yu-Gi-Oh! Trading Card Game.
Yugi Muto's appearance on the box cover for this video game is taken from the title page for Yu-Gi-Oh! Duelist - Duel 137 of the manga.
By imputing the passcode 25410867 into a computer at Kame Game, the appearance of Reshef the Dark Being will change into that of Goemon Impact, when the player faces him. Goemon Impact is a character from Konami's video game Legend of the Mystical Ninja.
The Millennium Guardians are based on the minor characters from the manga who only appeared in one page.