In a world where humans coexist with sentient monsters called Yoma (妖魔?) that feed on human innards, an organization has created an order of half-human, half-yoma warriors to protect humans from the yoma, for a large fee. The people of this world have dubbed these warriors "Claymores" based on their swords. They are also referred to as "Silver Eyed Witches", based on their appearance and seemingly cold nature toward others. Each Claymore has a rank number which is based on their strength and ability. There are 47 ranks corresponding to the number of regions of the land/world.
A Claymore known as Clare saves a small town by killing a Yoma living there, and meets Raki, a boy whose parents were killed by the Yoma. Out of gratitude, Raki ends up following Clare from town to town during her Yoma-killing jobs. The two travel together until they are separated when Clare is forced to battle a sadistic Claymore named Ophelia. Before parting, Clare promises to find him if she survives. The story becomes a tale of revenge, as Clare seeks to confront someone from her past.