It is the Middle Ages, and the remnants of mankind are plagued by paranoia and death. Spoken in fearful whispers, the word "Yoma" cuts a clear image into the minds of all: monstrous beings with an insatiable hunger for human flesh. But fear of their gruesome appetite is dwarfed by that of their ability to shapeshift and steal the memories of their last meal. Forever vulnerable to attack, humans live in unease, even among family.

There are few means to kill a Yoma. The Organization, informally known as "Claymore," is humanity's only line of defense, dispatching half-human, half-Yoma female warriors to purify villages of Yoma. A lonely and dangerous existence, death for these warriors comes with each new assignment. What time is found between trying battles and long, arduous travels is spent in ever-intensifying struggle to resist their Yoma blood and maintain their humanity. Villagers, knowing of this, pay for their security reluctantly and have only loathsome regard for their protectors.

Claymore follows the stoic and low-ranking member Clare in her daunting trek as she searches for personal vengeance. Along the way, she encounters many unexpected things about the world, from the camaraderie and hope held fast by her sisters-in-arms to the sinister truth behind the Claymore Organization.