The year is 1582 and Takeshi Kaneshiro as Samanosuke is the man who has just returned. The stage is set at the burning Honnoji Temple, as the famous Onimusha warrior Samanosuke Akechi fights. As he faces the demons in front of him, Samanosuke is compelled to move forward by hatred for his true enemy, the undying Nobunaga Oda, ever pursuing his crazed ambition. Samanosuke prepares for the long-awaited final battle against Nobunaga.

The year is 2004 and Jean Reno as Jacques Blanc is the man who has arrived. A peaceful French city is suddenly attacked by demons. In the blink of an eye, the city is transformed into a nightmarish nest of Genma demons who are slaughtering civilians and soldiers one by one. Within this nightmare, appears one man, a man who stands up against the Genma demons.

Nobunaga Oda has come back to unlife as the Demon Lord, and Samanosuke Akechi is there to stop him. As the final battle begins, a portal suddenly whisks Samanosuke away. Present day Paris suddenly gets a surprise when hordes of demons lay assault to the peaceful city. Jacques Blanc desperately fights alongside his fellow French soldiers, but they are no match for the fiends. Strangely enough, Samanosuke appears and slices the demons to pieces. Takeshi Kaneshiro returns as Samanosuke Akechi, the hero of the original Onimusha. Demon Siege also marks the arrival of Hollywood star Jean Reno as soldier Jacques Blanc. Now, the two heroes must fight together and take you on an epic adventure that goes beyond the boundaries of space and time.