The setting of Claymore's story is a fictional world with medieval technology. Politically, it appears to consist of a large number of scattered, apparently independent, towns. In this world, humans coexist with creatures called Yoma (妖魔, Yoma) sentient monsters that feed on human guts. The Yoma, being shapeshifters, are capable of taking on human form and living in disguise amongst humans. By consuming a human's brain, Yoma can also absorb their memories, allowing them to disguise themselves as specific people without alerting any of their close friends or family.

A nameless and highly secretive organization has created an order of superhuman warriors to protect humans from the Yoma. These warriors have come to be popularly known as Claymores, after the immense claymores they wield. Villages being attacked by Yoma hire Claymores to kill the Yoma for a large fee.

Despite saving humans on a regular basis, Claymores are often alienated from and feared by humans due to their incredible powers, their relation to Yomas, and generally aloof attitudes. Humans will often call them "silver-eyed witches/slayers" or "monsters". Family members of individuals impersonated by Yoma tend to be banished from villages for fear that they might be Yoma too. Claymores are often girls who suffered this fate or survivors of villages wiped out by Yoma.