Plot
Ryuko Matoi, a transfer student, arrives in Honnō City to find the murderer of her father Isshin Matoi. Her search leads her to Honnouji Academy, a militaristic high school ruled by Satsuki Kiryuin and the Elite Four student council, who use school uniforms called Goku Uniforms powered by a fabric called Life Fibers.
Following a failed attempt to challenge Satsuki on her first day, Ryuko stumbles across a sentient sailor uniform beneath the ruins of her father's home, which is a pure Life Fiber clothing called a Kamui (神衣) that increases her abilities while transformed. She names the outfit "Senketsu", and becomes armed with a scissor-shaped longsword called a Scissor Blade that can cut Goku Uniforms. Satsuki responds by donning her family's Kamui Junketsu to challenge Ryuko's powers. Ryuko is joined by her hyperactive classmate Mako Mankanshoku, a no-star student who lets Ryuko move in with her impoverished family, and her homeroom teacher Aikuro Mikisugi, who is actually an undercover agent of the anti-Life Fiber paramilitary organization Nudist Beach (ヌーディスト・ビーチ).
After battling numerous council members, including the Elite Four, Ryuko meets Nui Harime, a member of the global REVOCS Corporation (REVOCSコーポレーション) run by the academy's director and Satsuki's mother, Ragyo Kiryuin. Harime reveals herself as Isshin's killer, who stole the other Scissor Blade.
Satsuki leads her school to the upcoming Tri-City Schools Raid, a blitzkrieg raid to annex the remaining independent schools in Kansai, with the secret goal of destroying Nudist Beach's base in Osaka. After the raid, Ryuko learns that her father founded Nudist Beach and created Senketsu to fight the Life Fibers, which are actually parasitic aliens that prompted humanity's evolution to later feed on them.
Ryuko and Nudist Beach storm the Honnouji Academy festival held in Ragyo's honor before she awakens the Life Fibers. Satsuki betrays her mother, revealing her true goal to destroy the Life Fibers and avenge her father and younger sister, whom Ragyo ordered killed when Satsuki was young. Satsuki's plan backfires when Ragyo, revealed to be a human/Life Fiber hybrid, captures her while ordering the Life Fibers to consume every human. Ryuko discovers that she is Satsuki's presumed-dead younger sister and Ragyo's daughter; Ragyo's ex-husband, Sōichirō Kiryuin, faked his death and saved the infant Ryuko before taking the identity of Isshin as a disguise.
As Ragyo and the Life Fibers devastate Japan, the Elite Four and Nudist Beach rescue both Satsuki and Mako. Ryuko is brainwashed and bonded to Junketsu to pursue them, but Satsuki, Mako, and Senketsu manage to free Ryuko, who then regains the other Scissor Blade from Harime. Ryuko and Satsuki proceed to intercept Ragyo before she and the Primordial Life Fiber, the source of all Life Fibers, can reach Honnouji Academy to launch a command signal to a satellite for all Life Fibers to cover the planet and destroy it. However, Harime completes Shinra-Kōketsu, the ultimate Kamui, with Ragyo's secretary Rei Hououmaru offered as a sacrifice to activate it.
The heroes destroy the transmitter and extract Rei from Shinra-Kōketsu, only for Ragyo to restore its power by absorbing Harime and the Primordial Life Fiber. Ryuko pursues her mother into space after everyone offers their Goku Uniforms to power up Senketsu. She manages to have Senketsu absorb Shinra-Kōketsu to rescind the order. Defeated, Ragyo spitefully commits suicide while promising that the Life Fibers will one day attack Earth again. Despite being victorious, Senketsu begins breaking down from absorbing Shinra-Kōketsu and sacrifices himself to ensure Ryuko safely returns to Earth.
In the follow-up OVA episode, set two weeks after the battle with Ragyo, Rei Hououmaru uses leftover Life Fibers to create doppelgängers of Satsuki and the Elite Four in Junketsu and their original Goku Uniforms to disrupt Honnouji Academy's graduation ceremony and avenge Ragyo. The clones are defeated while Satsuki convinces Rei to abandon her struggle as Ryuko uses the Scissor Blades to finish off Honnouji Academy. Honnō City and the school sink into Tokyo Bay, as well as Ryuko's Scissor Blades. With their mission over, everyone can finally live a normal life free of the Life Fibers.