Loosely based on historical events that took place in England in the 15th century, known as the Wars of the Roses (a battle for power between the houses of Lancaster and York), Yu-Gi-Oh! The Duelists of the Roses sees the heroes of the Yu-Gi-Oh! manga and card game series, Yugi Muto and Seto Kaiba, assume the identity of the head of the Lancaster house (Red Rose, later the Tudor dynasty), Henry Tudor, and the leader of the Yorkist faction (White Rose), Christian Rosenkreuz, respectively. The player controls a Rose Duelist, who is initially sent by Henry Tudor (Yugi) and the Lancastrians to Stonehenge, with the mission of disrupting a barrier imposed by the White Rose forces. However, Rosenkreuz (Seto) arrives and offers the hero to side with the Yorkists. From that point on, the player can choose to follow either the Red or the White Rose, in two different scenarios.

Like most other Yu-Gi-Oh! video game adaptations, this is a strategy card game. The duels of the game take place on a 7x7 table; each player commands a "Deck Leader", who acts as the representation of the player character's hit point, as well as the central square on the map around which cards can be placed. Monsters can be navigated freely on the board, with the goal of surrounding and defeating the opponent's Deck Leader. Various field bonuses and card fusions are also present.