Five years have passed since the events of the first season. The existence of Amazons, human-eating creatures born from experimental cells, has become public knowledge, which led to the downfall of Nozama Pharmaceutical, the company that created them. In its place, a new government organization called 4C (Competitive Creatures Control Center) has risen to power, tasked with hunting down and containing the remaining Amazon threat. Compounding the crisis, the Amazon cells have mutated into a new lysogenic strain capable of infecting humans directly, transforming ordinary people into insane and bloodthirsty monsters.

The story centers on Chihiro, a young boy who appears human but is haunted by an uncontrollable urge to devour people. He rejects these instincts by fighting as Kamen Rider Amazon Neo alongside a small independent team called Team X. During a mission, Chihiro encounters Iyu, a girl who fights as the Crow Amazon. She is the first human he has ever met who does not trigger his cannibalistic impulses. What Chihiro does not realize is that Iyu is a Sigma-type Amazon, a walking corpse implanted with Amazon cells after her father killed her entire family. She has no emotions and feels no pain, making her a perfect weapon.

Chihiro’s world becomes more complicated when 4C captures him. The organization’s leader, Takeshi Kurosaki, recruits Chihiro and partners him with Iyu, forcing them to hunt other Amazons as a condition of their survival. Desperate to prove that the two of them are still human, Chihiro agrees to work for 4C. He grows increasingly attached to Iyu, hoping to help her recover her lost emotions and memory. Their relationship becomes the story's emotional core, with Chihiro striving to make Iyu smile while fighting his own degenerating body.

As the plot unfolds, the conflict expands to include the survivors of the first season. Haruka Mizusawa, formerly Kamen Rider Amazon Omega, has become a recluse, watching in despair as his dream of coexistence falls apart. His sister Mizuki now works for 4C and stands against him. Jin Takayama, Kamen Rider Amazon Alpha, has become even more unhinged, blinded and alone but more determined than ever to exterminate every last Amazon. The most tragic transformation belongs to Mamoru, the gentle Mole Amazon who once dreamed of peace; he has become the leader of an Amazon uprising, though even his rebellion is born of desperation rather than malice.

A devastating revelation redefines the conflict. Chihiro is revealed to be the son of Jin Takayama and Nanaha Izumi, born from the union of a human and an Amazon. His cells are a prototype for the lysogenic strain that is now infecting the human population, making him the "Original" responsible for the mutated plague. When Chihiro learns that he ate his own mother as an infant, he loses hope. During an attempted isolation by 4C, he undergoes a complete transformation into a monstrous form with six limbs resembling wings, killing nineteen people in a single rampage before fleeing in horror at what he has become.

The season builds toward an inevitable tragedy rather than a heroic victory. Haruka submits to his sister's judgment regarding his future. Jin confronts Nanaha one final time to end their shared suffering. The original extermination squad faces Mamoru in a heartbreaking battle between former friends. Chihiro and Iyu struggle to hold onto their fading humanity in their remaining time, knowing that neither side of the war will accept them. The series concludes with no clear heroes or villains, only broken individuals trying to survive the consequences of mistakes made years ago. The animosity between humans and Amazons is greater than ever, and the central characters face their final judgment without hope of rescue.