"Kill la Kill" is set in a dystopian world where the elite Honnouji Academy is governed by a strict hierarchy enforced by its student council. The council members wield powerful uniforms called Goku Uniforms, which grant them superhuman abilities. These uniforms are created from Life Fibers, a mysterious alien material that enhances strength and durability. The academy's iron-fisted rule extends beyond its walls, controlling the surrounding city of Honno City.

The protagonist, Ryuko Matoi, arrives at Honnouji Academy seeking answers about her father's murder. Armed with a sentient weapon called Scissor Blade, Ryuko challenges the student council and its president, Satsuki Kiryuin, who is the primary antagonist. Satsuki, clad in the most powerful Goku Uniform, Kamui Junketsu, commands the academy with an unwavering resolve to achieve her own hidden agenda. Ryuko discovers a Kamui of her own, Senketsu, a sentient uniform that bonds with her and grants immense power but requires her blood to function.

As Ryuko battles her way through the student council's elite Four Devas, she uncovers the truth about Life Fibers and their connection to humanity. Satsuki's mother, Ragyo Kiryuin, is revealed as the mastermind behind the Life Fiber experiments, aiming to use them to dominate the world. Ragyo's plans involve harvesting Life Fibers from humans, a process that would result in widespread destruction. Ryuko and Satsuki, despite their initial rivalry, form an uneasy alliance to stop Ragyo and her organization, REVOCS, from achieving their goal.

The narrative explores themes of rebellion, identity, and the corrupting influence of power. Ryuko's journey is one of self-discovery, as she grapples with her own origins and the true nature of her connection to Life Fibers. Satsuki, initially portrayed as a cold and calculating leader, is revealed to have her own motivations rooted in a desire to protect humanity from her mother's schemes. The series culminates in a climactic battle where Ryuko and Satsuki confront Ragyo and her ultimate creation, the Original Life Fiber, leading to a resolution that reshapes the world and their understanding of it.