In your return to Battle City, you begin another mission to retrieve stolen millennium cards that can destroy the world. Yu-Gi-Oh! Reshef of Destruction features an all-new storyline that sets you off on a quest to stop Reshef from drowning the world in darkness. Since the game's battles are fought with cards, you must build a strong deck from 800 different cards (including all three Egyptian god cards) to even stand a chance against your enemies.

The story takes place after the battle in Battle City. The protagonist, Joey and Yugi were on their way to participate in a tournament at the Duel Express. However, the other Yugi disappears along with the Millennium Puzzle. As the three search for the puzzle, Ishizu appears and tells them a terrifying truth. Someone has performed a ritual to resurrect the Great Evil God, Reshef, into this world. As a result, the three god cards lost their power and were turned to stone. The only way to seal the Great Evil God is to recover the Millennium Items scattered around the world and restore their power to the three God cards. After hearing Ishizu's request to save the world from the Great Evil God, the protagonist and his friends set out on a journey to find the Millennium Items. However, Sol Chevalsky, the man who resurrected the Great Evil God, sends assassins to challenge the protagonist and his team...