Yuugi Mutou is a naïve and lonely high school student who is fascinated by games. While staying with his grandfather, the owner of a game shop, he comes across an ancient Egyption relic known as the "Millennium Puzzle." Rumored to grant any wish to those who solve the Puzzle, Yuugi becomes determined to solve it to wish for some friends. After years of struggling, Yuugi manages to complete the puzzle and mysteriously finds that his wish has been fulfilled.

Meanwhile, a new card game known as "Duel Monsters" starts rising in popularity. In this game, players called duelists fight against each other with "monsters" by using magic and trap cards to foil their opponent's plans. Yuugi quickly becomes skilled at the game and lives a peaceful life with his newfound friends.

However, Yuugi's peace is short-lived. The undefeated duelist and egocentric billionaire Seto Kaiba suddenly abducts Yuugi's grandfather, forcing him to duel against the rare "Blue Eyes White Dragon'' card. Yuugi is thrown into a new world of fierce battles and the stakes continue to rise as dark forces interfere from the shadows. After unexpectedly defeating Kaiba with the help of his "other self"—the spirit of a nameless pharaoh—contained in the puzzle, he unofficially becomes the top duelist known as "The King of Games." However, this new title will attract covetousness and Yuugi will have to use all his intelligence and willpower in order to protect what he holds the dearest to him.

Yu☆Gi☆Oh! Duel Monsters loosely adapts chapters 60-343 of the source manga while adding original events and characters not present in the manga.