"I make my own decisions, and see them to the very end. I had to find my resolve, so I could remain true to myself."
~Saya Kisaragi [Blood-C]
Saya Kisaragi is the daughter of the priest at the local shrine, whose duty it is to slay the Elder Bairns, creatures who drink the blood of humans. It is what her mother did before she died, and now Saya is the only one who can slay them. By day she seems to live a normal life of a high school girl, though Saya does seem to be rather clumsy, and completely oblivious to many remarks that are made around her, especially concerning boys that seem to like her. Since neither she nor her father are capable cooks, she eats breakfast every morning at Guimauve, the cafe next to the shrine.
The owner, Fumito Nanahara gives her a sweet called Guimauve, named after the cafe, as well as preparing her lunch. When she fights, her abilities are human or slightly above normal human abilities, until her eyes glow red. She then seems to become more serious, and much stronger and faster. Her father, Tadayoshi Kisaragi, provides her with a sword with which she fights. As the series progresses, Elder Bairn attacks become more frequent, even occurring during the day and at the school which Saya attends. As more and more people die or go missing, Saya begins to have strange visions and flashbacks, along with headaches that occur when she tries to remember certain things.
A small cute dog appears, who states (Yes, he talks. It is hinted that he is Kimihiro Watanuki) that he is trying to grant her wish. Saya made a promise to protect everyone, but cannot remember to whom she promised. She realizes she cannot remember her mother's name or appearance. This, and some other things, he tries to get her to realize, but she is still unable to remember anything. Tired of waiting for Saya to remember, Kanako Tsutsutori (along with Nene Motoe, Nono Motoe, and Shinichirou Tokizane) try to force Saya to remember by having her drink the blood of an Elder Bairn. Tsutsutori, however, overdoes it, and Saya becomes inebriated. They tell Saya that they are all "cast members" who were hired to play many roles, in which she is the "lead star".
Several characters who were previously thought to be dead are shown to be alive, namely Tokizane, Nono, and Nene. They are confronted by Yuuka Amino and Itsuki Tomofusa, who question why they tried to ruin the project. Fumito Nanahara joins them, and it is revealed that he is the one who arranged for Saya to be brought there. He has been controlling the Elder Bairns by using Saya's blood, and has a Cerberus bairn kill Tokizane, Nono, and Nene for trying to make Saya remember. Saya remembers drinking the blood of the Elder Bairns that she defeated. Every time, Fumito would make Saya forget again. Kanako runs to Tadayoshi, who embraces her before killing her and drinking her blood. Tadayoshi is half human, half Elder Bairn. Saya begins to remember her past self, and of the terms to the wager which she and Fumito had agreed; By erasing Saya's memories and planting fake ones, would she change? Or would she revert to her old, murderous self?
Saya cannot kill humans, and agreed to protect them, but it is not revealed with whom she made this contract, or who made the stipulation that she couldn't harm humans. Saya said she wouldn't change, but Fumito said he would arrange it so she could attack humans if she won the wager. He does not say what he gets if he won the wager. Saya defeats Tadayoshi, crying as he dies and calling him "Father". As Saya chases after Fumito, he leaves a strange bunny Elder Bairn, which Saya slices in half. It multiplies and slaughters the town full of people, many whom are screaming that it was not part of the contract. While still running after Fumito, Saya kills the original, and the rest of the strange bunny bairns die.
Fumito begins to fly away in a helicopter, and Saya jumps high enough to finally kill him, but he shoots her in the head, apparently blowing half her head off. As she falls into the ocean below, Fumito comments, very calmly, that the ingredient in Guimauve was the blood of the Elder Bairns, and he had been told that it tasted like human organs. He wonders if she ever will be able to kill humans, as she could have the real thing then.
As the helicopter flies away, Saya remains floating in the lake. She is still alive, and rests on shore waiting for her wounds to heal. After what seems to be a day or two, Saya rips off part of her school uniform skirt and bandages her still bleeding left eye. The dog remarks that, before Saya was captured, she made a wish: "I want to stay myself". He says he has fulfilled this wish of hers, but it is time for her to reach for the next wish.
As the credits begin rolling, her sword breaks in half. She throws it away, and starts running away from the area, presumably to search for Fumito.