In a world with an alternate history, a great war finally comes to an end leaving the earth diseased and polluted. The geneticist Dr. Azuma vies for support from the government for his neo-cell treatment that he claims can rejuvenate the body and regenerate humankind. The government leaders, guarding their own deeply entrenched powers, turn down the professor. Driven to complete his work, Dr. Azuma accepts a secret offer from a sinister faction of the powerful military. After an incident occurs in Dr. Azuma's lab, a race of mutant humans known as the Shinzo Ningen are unleashed upon the world. Now only the warrior known as Casshern, reincarnated with an invincible body, stands between the Shinzo Ningen and a world on the brink of annihilation.

In war-torn Japan, the Tokugawa Shogun, desperate to restore peace to his people, orders the assassination of the hostile warlords. A beautiful young woman is raised from birth with nine other orphans, to become an assassin. Her name is AZUMI, the ultimate assassin.