Two years have passed since the wave of murders committed by the Unidentified Lifeforms was brought to an end. A new series of impossible killings grips the city, carried out by unseen assailants the police codenamed the Unknown. These monstrous beings are, in truth, the Lords, angelic warriors who view themselves as protectors of humanity, systematically eliminating specific humans who possess the potential to awaken a power known as Agito.

The narrative centers on Shouichi Tsugami, a cheerful young man with no memory of his past. He lives on a farm attached to the Misugi household, unaware that when an Unknown attacks, he is compelled to transform into the superhuman warrior Kamen Rider Agito. His powers are a mystery to him, tied to the very amnesia that erased his identity. In parallel, Makoto Hikawa is a sincere but often clumsy police officer selected to wear the G3 armor, a powered exosuit developed by the brilliant Sumiko Ozawa. Modeled after the legendary Kuuga, the G3 is the police's official counter-weapon against the Unknown, though it is often outmatched by the raw power of the Lords. The third pillar of the story is Ryo Ashihara, a former university swimming champion whose life collapsed after a motorcycle accident caused his latent powers to manifest incompletely. He transforms into the pained and bestial Kamen Rider Gills. Driven by loneliness and the mysterious suicide of his father, Ryo searches for answers, believing the key lies in the Akatsuki, a sunken cruise ship from which Shouichi was rescued.

The series establishes a unique dynamic where the three riders are not initially allies. The police, particularly the ambitious and suspicious Tooru Houjou, view Agito as a dangerous rogue element to be captured. Makoto struggles with his duty as a member of law enforcement versus his growing belief that Agito is protecting people. Ryo, suffering painful side effects from his transformations, lashes out in confusion. Their conflicts deepen as the mysterious OverLord appears, a boy who shares a psychic link with Ryo and holds secrets of the Lords. As Shouichi gradually recovers fragmented memories through the psychic abilities of Mana Kazaya, the daughter of the man who took him in, the story reveals the horrifying truth of the Akatsuki incident. The ship was carrying individuals with the Agito seed, and the Lords, servants of a God-like entity who fears humanity's evolution, have been systematically hunting the survivors.

A significant mid-series arc involves the introduction of Kaoru Kino, a surgeon and another Akatsuki survivor who transforms into Another Agito, a version of the power twisted by revenge. Believing that the Agito power brings only tragedy, he seeks to eliminate other Agitos, forcing a three-way conflict between justice, duty, and survival. Simultaneously, the G3 system is upgraded to the powerful G3-X, while Hikawa and Ozawa face internal police conspiracies. The narrative builds toward the revelation of the mysterious youth seen throughout the series as the manifestation of the OverLord of Darkness, the creator of the Lords. He seeks to destroy all Agitos, viewing them as an abomination that threatens the natural order.

The final arc sees the Lords escalate their attacks, unleashing the powerful El Lords. Shouichi evolves into Burning Form and ultimately Shining Form, representing the peak of his potential. Ryo overcomes his agony to achieve Exceed Gills, a stabilized version of his form. Hikawa masters the G3-X, fighting purely as a human equal to the superhuman warriors. The three riders unite to storm the OverLord of Darkness's dimension. They learn that Agito is not a curse but the next step in human evolution, a power that allows humanity to carry its own light into the future. The series concludes not with the destruction of the OverLord of Darkness, but with a stalemate, forcing him to acknowledge humanity's right to evolve. Shouichi regains his past but chooses his present family, Ryo finds peace as a mechanic, and Hikawa continues his duty, knowing that humanity is now strong enough to face its own destiny.