In the near future, Tokyo was left flattened as a result from a great earthquake. A new city, MegaTokyo, was then recreated due in no small part from the aid of a multi-million dollar company, Genom Corp. Genom created and mass-produced biomechanical creatures called Boomers to aid in the restoration of MegaTokyo. When the Boomers began to run out of control, the ADPolice at first tried to stop them, but they proved to be far more difficult to deal with than was first imagined. Under the ever looming Boomer threat, a group of four girls from varying degrees of society banded together. Calling themselves The Knight Sabers, they were the only ones with enough firepower and resourcefullness to defend the fledgling MegaTokyo from Genom and its berserk Boomers.
Eleven years after the introduction of internet-connected, augmented reality eyeglasses and visors, Yoko Okonogi moves with her family to Daikoku City, the technological center of the emerging half-virtual world. Yoko joins her grandmother's "investigation agency" comprised of children equipped with virtual tools and powerful metatags. She quickly crosses paths with Yoko Amasawa, an expert hacker of the virtual environment, as Amasawa relentlessly seeks to "unlock" the mystery of a computer virus that emerges from an inaccessible corrupted space.
The Japanese Ministry of Defense has an anti-paranormal special forces group called the Paranormal Disaster Countermeasure Headquarters. They're the ones responsible to protect Japanese soil and its people from supernatural and paranormal events. However, things didn't go so well in one of their missions, which leads to intervention by the Ministry of Enviroment's Supernatural Disaster Countermeasures Division after the PDCH has sustained large numbers of casualties battling demons.
Tokiha Mai and her sickly younger brother, Takumi, have received a scholarship to attend the prestigious Fuuka Academy. On the way, the ferry they are travelling on becomes the site of a destructive battle between two girls wielding apparently supernatural powers. This is only the beginning of their troubles, as Mai learns that she herself possesses these powers - the powers of a HiME.