Dead or Alive 4 focuses on the story of Helena Douglas taking over the mantle of the Dead or Alive Tournament Executive Committee as its second chairman, determined to fight against the corruption in the organization. After losing both her father and her beloved mother to the darkness of conspiracy, Helena chose to place herself in the middle of the maelstrom in order to put an end to the chain of tragedy once and for all.

The man who holds the true power at Doatec, Victor Donovan, locked himself in the Bio Lab Core again to continue coveting his dream of creating the perfect human weapon. His new project, code named "Alpha-152", is the result of the ultimate evolution of hyper-cloning technology, birthed from a DNA sample of Kasumi.

The main storyline continues with the war between the Doatec and the Mugen Tenshin Ninja Clan. After Ayane successfully defeats Doatec's last creation, Omega, Hayate returned to the Mugen Tenshin clan, taking over the leadership. Now leader, his heart burns with the desire of revenge as he goes on a quest to put an end to Doatec. During the fourth tournament, Hayate brought together the most powerful group of Ninjas known to man. He is accompanied by Ayane, Ryu Hayabusa, and other members of the Mugen Tenshin clan; Kasumi, though reluctant, is dragged into the events herself as she follows her brother.