Youko Nakajima has only ever wanted to be normal. She does what she is asked, gets good grades, is the class president, and even helps her classmates whenever she can—but because of her red hair, she has never fit in. With her pushover attitude, Youko lets classmates take advantage of her, so she has nobody she can really call a friend. But on an otherwise ordinary day, a man who claims to be from another world barges into Youko's classroom and bows before her. This elegant blond-haired man, Keiki, claims that Youko is his master and belongs on the throne of his kingdom. However, their first meeting is cut short as Keiki has been followed by otherworldly beasts called youma. He is able to escape with Youko into his own realm, but two other classmates—Ikuya Asano and Yuka Sugimoto—are caught up in the madness as well. Unfortunately, their troubles have only just begun, as the youma attack leaves them separated from Keiki. Alone in this strange new land, these ordinary students must learn to fend for themselves or die.

Texhnolyze takes place in the city of Lux, a man-made underground city that has crumbled after years of neglect and lack of repairs. Citizens of Lux have come to refer to their home as simply "The City" and treat it as though it has a mind and will of its own. Three major factions battle to control Lux: Organo, a group of "professionals" who collaborate with the criminal underworld that controls Texhnolyze (prosthetics), the Salvation Union, a populist group that seeks to disrupt Organo's business, and Racan, a collection of young individuals with Texhnolyzes that use their abilities for personal gain. Ichise was once an orphan who has made a place for himself in Lux as a prize fighter. One day, a fight promoter grows angry with him and the altercation that follows results in Ichise losing an arm and a leg. Before death can take him, Ichise is found by the scientist Eriko Kamata, who uses him as a test subject for her newly designed Texhnolyze. With these powerful new limbs at his disposal, Ichise begins to work for Oonishi, the leader of Organo. He soon meets a mysterious young girl, Ran, who has the power to see possible futures. Together, they soon realize that Lux is on the brink of war and collapse, and that they may be the only ones who can save The City.

In Doumori, an imbalance of spiritual forces threatens to plunge the small city into complete chaos. Thankfully, for the students of Doumori Elementary School, new teacher and exorcist Meisuke "Nube" Nueno is determined to prevent the malignant spirits—known as youkai—from accomplishing their evil deeds. The first student who catches Nube's attention is transfer student Hiroshi Tateno, who displays inexplicable outbursts of anger, often lashing out at his classmates. When they find out that Hiroshi is possessed by a youkai, Nube manages to free his student thanks to the demonic power sealed in his left hand. However, a youkai hiding behind the appearance of doctor Kyousuke Tamano bursts onto the scene and quickly abducts Hiroshi. Helped by his student Kyouko Inaba and his expertise in the occult, Nube quickly uncovers Kyousuke's sinister plans. Rushing to Hiroshi's rescue, Nube will show once more that he will stop at nothing to protect his beloved students against all supernatural threats.

Panty and Stocking Anarchy, the angel twin sisters, have even more ghosts to exorcize in Daten City, thanks to the failed opening of the Hell Gate. They must continue their ghost hunt alongside their longtime rivals, the sisters Scanty and Kneesocks Demon, who must earn Hell Coins to return to Hell. On top of that, the Demon sisters are staying at the church with Garterbelt, the priest in charge of the Anarchy sisters. These two polar opposite duos will have to set aside their differences if they wish to collect enough Heaven and Hell Coins to complete their mission and return to their respective realms.