In a world where humans coexist with creatures called Yoma (妖魔?) sentient monsters that feed on human innards, a nameless and highly secretive 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 as "Claymores" based on their gargantuan, unsheathed swords, or the "Silver Eye Witches", based on their appearance and seemingly cold nature toward others.
After the death of her motherly figure, Teresa, at the hand of Priscilla, Clare voluntarily joins the Organization to seek vengeance. In a small town terrorized by a yoma, she meets and befriends a kind-hearted, albeit naive, young man named Raki. 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. After defeating Ophelia with the help of Irene, her plan of reuniting with Raki is disrupted by the agents of the Organization, who inform her that Isley, Abyssal One of the North, is amassing an army of Awakened Beings. Unwillingly, she is sent to the north along with twenty-three other Claymores. Knowing full well that they have been ordered on a suicide mission, Clare and her comrades come up with a plan to feign their own deaths and go into hiding with the help of Yoki suppression pills. Despite their efforts, only seven Claymores, including Clare, survive the brutal battle.
After hiding seven years with the other six survivors, Clare finds evidence Raki survived and convinces her comrades to travel south with her to look for him. However the other survivors' main aim, under the command of former #6, Miria, is to overthrow the Organization that betrayed them. After rescuing the fortified city of Rabona from an awakened being, the group hears about the true nature of the Organization and the world from Miria. She reveals that the Organization's goal to protect humans from yoma is a sham to cover up their experiments to create controllable awakened beings. These, she reveals, will be used fight the Organization's off-island enemies, who have as their allies monstrous creatures called "Dragon-kin". The purpose of the Organization is nothing less than developing controllable awakened beings to fight the Dragon-kin, for which purpose the island serves as their "lab". However Miria knows little of the outer world, revealing that it consists of lands outside the island where two sides are battling for supremacy.
Soon after the battle Clare learns that Raki was in Rabona the year before with a small girl, which troubles her. Unknown to Clare, this girl is none other than her archenemy, Priscilla. Clare then leads a group of survivors west to find Raki and along the way meets Rubel, her former handler. He reveals that he suspects that Riful, the Abyssal One of the West, has captured Renee, the "Eye" (long-range yoki detector) of the organization to obtain something. It is revealed that this is likely "Rafaela's shell", the body of Rafaela, who was equal to her sister, the awakened number one, Luciella. After learning that Riful is attempting to awaken Rafaela and make her an ally, Cynthia, another survivor, correctly guesses that Rubel is in fact a spy. He urges them to attempt to destroy the organization, save Rafaela, and warns them not to let the organization find out about their partially awakened members.
Two of the other survivors, Helen and Deneve, head south from Rabona and discover the existence of Abyss Feeders, part human/part awakened being hybrids assigned to kill Isley, the reigning Abyssal One of the South. After a tough battle, Isley falls in battle. Soon after the Organization unleashes more Abyss Feeders and warriors No 1 and 2, identical twin sisters Alicia & Beth, in the west. Their orders are to find and kill Riful before she awakens Rafaela and destroys the island's balance of power.