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.

When the governor of Tokyo is killed in his campaign for election, the former CIA agent Travis Hunter is assigned to find the responsible working together with the rookie FBI agent Sean. Travis was raised in Japan, has great connections with the underworld of the streets and is a master in sword and martial arts, trained by a former member of Yakuza. Travis discloses that there is a war between the old and traditional members of Yakuza and the new generation leaded by the deranged and sick Kuroda, who has associated to the Chinese Tong mobster Chen in a powerful drug dealing business. When his fiancée Nayako is brutally and cowardly murdered by one of Kuroda's men, the mission of Travis becomes a personal issue and he seeks revenge.