The start of Hanae Ashiya's high school career has not been easy—he has spent all of the first week in the infirmary, and his inexplicable condition is only getting worse. The cause of his torment is the mysterious fuzzy creature that has attached itself to him ever since he stumbled upon it the day before school began. As his health continues to decline and the creature grows in size, Hanae comes across a flyer advertising an exorcist who expels youkai. Desperate and with nothing left to lose, he calls the number and is led to the Mononokean, a tea room which suddenly appears next to the infirmary. A morose-sounding man, Haruitsuki Abeno, reluctantly helps Hanae but demands payment afterward. Much to Hanae's dismay, he cannot afford the fee and must become an employee at the Mononokean to work off his debt. And to make things worse, his new boss is actually one of his classmates. If Hanae ever hopes to settle his debt, he must work together with Abeno to guide a variety of dangerous, strange, and interesting youkai back to the Underworld. [Written by MAL Rewrite]

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.

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.

Two bonus episodes that take place during the course of the series, approximately halfway through it seems. They are entitled 'Everything you always wanted to know about Nereids (but were afraid to ask)' and 'Heaven can wait for Maia Mizuki'. These stories are more lighthearted and comedic in tone, bordering on silly.