When a new disease called the Bugster Virus or "Game disease" begins infecting people across japan, the ministry of health works with GEMM Corp., a major video game company, to create the Cyber Rescue Center or "CR" and recruit a group of Doctor Riders including Emu Hojo AKA Kamen Rider Ex-aid, a medical intern with incredible gaming skills, and Hiiro Kagami AKA Kamen Rider Brave, a young genius surgeon who has never had a failed operation. Together with the help of Poppy Pipopapo, a Bugster reprogrammed to help them, they set out to cure the japan of the Bugster Virus. But they soon find that they aren't the only Doctor Riders out there and that the CEO of GEMM Corp. has his own motives in all this that could threaten their mission.
Amanogawa High School has become the center of strange happenings, and things only get stranger when the bad boy styled transfer student Gentaro Kisaragi attempts to make friends in his own unique way, reuniting with childhood friend and self-professed space travel otaku Yuki Jojima, all while gaining the ire of loner Kengo Utahoshi. When the campus becomes overrun with monstrous constructs called Zodiarts, Kengo and Yuki attempt to use the strange devices they have found in the Rabbit Hatch lunar base that they access through a locker on an off-limits part of campus to fight them. However, Gentaro interferes in their plans, in part due to Kengo's body unable to handle the strains of battle, and uses the devices to transform into Fourze. Upon learning of other heroes called Kamen Riders, Gentaro creates the Kamen Rider Club whose membership includes Yuki, Kengo, the school's queen bee Miu Kazashiro, Miu's jock ex-boyfriend Shun Daimonji, garishly styled social butterfly JK and goth girl Tomoko Nozama. Later joined by Ryusei Sakuta, a transfer student who transforms into Kamen Rider Meteor, and their teacher Mr. Chuta Ohsugi, the Kamen Rider Club and Kamen Rider Fourze learn of the Horoscopes, an evolved group of Zodiarts who have been orchestrating events on the school grounds to build up their ranks. As the battle escalates, the Horoscopes sets their motions to their final phase of their master plan before Kengo discovers his true existence.