Onimusha 3: Demon Siege is a 3D action game set in 16th century Japan and present day France. After confronting Nobunaga at the Honnō-ji Temple Samanosuke is defeated in a battle that follows between him and the Genma leader. Before Nobunaga can kill him he is whisked to present day Paris where he soon discovers that the Genma have invaded the city. Here he meets the Frenchman Jacques Blanc (modeled after actor Jean Reno) and saves him form a group of Genma. Shortly after this meeting Jacques is transported to 16th century Japan. The two of them now have to find a way to get back to their own time and stop the Genma and Nobunaga.

In the game the player take control of Samanoske and Jacques and later on in certain areas Michelle (Jacques' girlfriend). Gameplay involves mostly defeating a large number of normal enemies as well as bosses. Both Samanoske and Jacques can absorb the souls of defeated monsters to upgrade their weapons and armor. Michelle can’t be upgraded but she can absorb souls through a neckless that can later be transferred to Samanoske or Jacques. Samanoske can use three Oni swords, Jacques has three Oni whips and a hand gun to finish of enemies and Michelle can use guns and grenades. Sometimes items have to be retrieved before the player can advance and occasionally small puzzles have to be solved. The Tengu Ako has been tasked by the Oni to help Jacques and Samanoske and can transport herself and items between the two different times. Sometimes Items that have to be used by Samanoske have to be found by Jacques and transported via Ako.

The game features a new control scheme and a fully 3D graphic engine, as opposed to the 2D pre-rendered graphics of the first two. The music is a combination of European-style orchestral writing and Japanese instruments.