In this version of the franchise, Doctor Azuma is researching artificial stem cells, or "Neo Cells", that can be used to create replacement organs; the cells can only be found within the "original humans" in Zone 7 of Eurasia, recently conquered by the Eastern Federation after it defeated "Europa".
Afterwards, Azuma's son Tetsuya, who had volunteered to fight in the war against the Doctor's wishes, is assigned to a hellish mission in Zone 7 that ends in his death. Meanwhile, Azuma is facing the wrath of the government because he is unable to create limbs from the Neo Cells that can be used by humans.
Suddenly, a lightning bolt — that is, a literal giant stone lightning-bolt symbol — appears from nowhere and strikes the lab, causing the limbs to quicken and recombine into Artificial Humans. The Federation military quickly attempts to massacre them, but a quartet escapes, taking Azuma's wife as a hostage; they find an abandoned Europan factory, dub themselves "Neo-Sapiens", and decide to Kill All Humans with the Mecha-Mook army they manufacture.
Shortly after the kidnapping, Azuma resurrects Tetsuya within the vats the Neo-Sapiens arose from — despite the objections of Tetsuya's ghost. Inevitably, Tetsuya comes into conflict with the Neo-Sapiens and their leader, Burai.
The film drew international attention as soon as footage was released for its stylized visuals and impressive action scenes. The themes of the futility and dehumanization brought about by war added spice. However, the Darker and Edgier tone, shameless use of Deus ex Machina to move the plot, and esoteric ending dimmed enthusiasm once the film was released.
Casshern contains examples of the following tropes:
- Came Back Wrong: Tetsuya's ghost was literally pleading for his father not to resurrect him; after his rebirth, he had to be encased in experimental Powered Armor to control his new strength, and struggled with a Damaged Soul. Similarly, each of the named Neo Sapiens has only vague visions of their former selves. And when Luna is resurrected with Burai's blood, she is possessed by his hatred.
- Cloning Body Parts: Dr. Azuma's plan for the Neo Cells, which would allow the aging leadership of the Eastern Federation to have a new lease on life.
- Darker and Edgier: It's a significantly more bleak, moody and somber take on the concept than the original anime, comparable to the anime reboot that did much the same thing years later.
- Dehumanization: The concept of the "orignal humans," or "True Humans" — which implies an ancestral race entitled to treat baseline humanity as disposable. Or be treated that way themselves, since the True Humans of Zone 7 were slaughtered for their Neo Cells. In either case, the reanimated Neo Sapiens pay it forward in turn.
- "Everyone Comes Back" Fantasy Party Ending: During the Gainax Ending, the Going Cosmic scenes are intercut with flashes of the entire cast - including the villains - reunited for a dance party/picnic in a beautiful garden. Since it is implied that not only are they all dead and in heaven, but that they are reincarnated souls that have just finished another tour, the tone is oddly appropriate.
- Human Resources: The Neo Cells were harvested from residents of Zone 7; the Neo Sapiens were reborn versions of some of the victims.
- Obligatory War Crime Scene: Tetsuya is unable to escape joining in the atrocities committed by the Eastern Federation army. Most significantly, he chooses to shoot a helpless civilian when his commanding officer is threatening a fellow soldier with death if he doesn't kill them himself. And the person Tetsuya killed was Burai's wife before his rebirth as a Neo-Sapien.
- Shell-Shocked Veteran: Tetsuya joined the Asian Empire military to prove himself, and was killed in action by a booby trap. After being revived as Casshern, he experiences post-traumatic flashbacks to his wartime experiences, including the atrocities he committed.