Yuki Cross's earliest memory is of being attacked by a vampire and saved by Kaname Kuran, also a vampire. Ten years later, Yuki and a vampire hunter, Zero Kiryu attend Cross Academy as school guardians protecting the "Day Class" and the "Night Class" from each other to keep vampires secret. The story follows Yuki's discovery that her childhood friend, Zero, has spent the last four years trying to fight his transformation into a vampire, and he has finally succumbed. Yuki struggles to help Zero fight his bloodlust and to recover her own lost memories, while suspecting that Kaname knows more than he is saying.

When his uncle, Rido Kuran, returns to kill Yuki, Kaname is forced to reveal her secret by biting Yuki and awakening her true nature as a vampire, returning her memories of being Yuki Kuran, his younger sister. Rido is killed by Zero and Yuki while Kaname faces and destroys Rido's allies, the Vampire Council, revealing himself to be one of the original vampires and the founder of the Kuran clan. Yuki and Zero part as enemies after Zero reveals he intends to end everything, by killing all purebloods, even her. Yuki leaves with Kaname and they return to the Kuran family home. The story restarts a year later with Yuki's dealing with vampire society and new enemies, such as Sara Shirabuki.