The Earth's most cogent company, otherwise known as the Smart Brain Corporation, is attempting to secretly kill of the human population by using the next stage in humanity's evolution, the Orphnoch. They develop three suits of power armor, called Rider Gear, to recover and guard the Orphnoch King, who can cure a flaw within the Orphnoch DNA, which causes their genetic structure to break down. The Rider Gears are stolen by Hanagata, the Goat Orphnoch and former President of Smart Brain Corporation. He sends them to his foster children (which are called the Ryuseiji, after the school they attended) so they can stop the Orphnoch from attaining their objective. However, the Rider Gears were designed to be worn by Orphnoch, humans are unable to activate the systems without undergoing genetic modification.

A young loner, Takumi Inui, is unwillingly drawn into the conflict between the Orphnoch and humans and becomes Kamen Rider Faiz to save the life of Mari Sonoda, one of the Ryuseiji. To retrieve the Faiz Gear, the Smart Brain Corporation begin targeting him. Nevertheless, there is division amongst the Orphnoch, as those who wish to co-exist with humans rather than kill them. begin resisting Smart Brain, who in turn targets them as well. Most of these "renegade" Orphnochs are either killed, remain neutral or begin siding with the Ryuseiji against the Smart Brain Corporation.

When the Tokyo police discover the Orphnoch are behind a series of strange murders, they begin plans to defeat the creatures, completely unaware of the various groups involved. The police conduct experiments on captured Orphnoch in an attempt to discover a method of destroying them, though it doesn't produce positive results. The Orphnoch King eventually awakens within a young boy named Teruo, whom Naoya Kaido and Keitaro Kikuchi saved and befriended. Now, it is up to the bearers of the Rider Gears to band together and battle for the survival of humankind.