After the events of the previous two incidents involving the Karakasa umbrella and the Fire Rat, a fragile peace has finally returned to the Ooku, the inner palace of the Edo Castle. However, the Medicine Seller remains vigilant, sensing a lingering and unsettling presence beneath the surface. The apparent calm is shattered when Empress Sachiko, the wife of the ruling emperor, dies in despair shortly after giving birth to a long-awaited male heir. Her profound regret over an irreparable sacrifice, combined with the anger of not being rewarded for her duty, begins to fester into a potent resentment.

This deep-seated grudge awakens a monstrous and wrathful Snake God, or Hebigami. As the Ooku is plagued by unnatural earthquakes, falling scales, and the death of a maid whose body is found twisted as if crushed by a giant serpent, the Medicine Seller rushes to confront the source of the terror. He is immediately faced with an enormous, snake-shaped mononoke. His demon-slaying sword is useless until he can discover the entity's three elements: its Form (Katachi), its Truth (Makoto), and its Reason (Kotowari). To find these answers, he must delve 150 years into the buried history of the Ooku, uncovering a shocking and fundamental truth about the palace's dark origins that threatens the very soul of the nation.

The central conflict revolves around the Ooku itself, a place where women have long been treated as mere vessels for securing the imperial bloodline, and it is from this sea of accumulated anguish that the Snake God is born. The Medicine Seller, voiced by Hiroshi Kamiya, finds himself in an unprecedented crisis, cornered by a divine being fueled by centuries of sacrifice and fury. He must risk everything to confront this mononoke, which represents the very essence of the Ooku's grim history, while a priest of the Ooku's faith, Hokuto Mizorogi (voiced by Kenjiro Tsuda), watches the events unfold with a solemn expression. This final chapter of the film trilogy pits the enigmatic protagonist against his most formidable foe yet, as he struggles to survive and uphold his duty. The narrative also features key characters from the inner palace, including the late Empress Sachiko (voiced by Atsumi Tanezaki), her nursemaid Tokiwai (voiced by Fumi Hirano), and the Third Empress (voiced by Miyuki Sawashiro).