Tsukune Aono, an average teenager, is unable to get into any local high schools due to his poor grades. However, his parents are happy to have him enroll in a private school called Yokai Academy, which Tsukune discovers is a boarding school for monsters. The school teaches monsters how to coexist with humans, including disguising as them, but any real humans on campus are to be killed. Although fearing for his life, Tsukune befriends a beautiful vampire girl Moka Akashiya, who likes the taste of his blood. Fighting a school bully, Tsukune accidentally removes the rosary around Moka's neck, and discovers she turns into her true, powerful vampire self.
Because of Moka, Tsukune decides to stay at Yokai, and becomes friends with originally antagonistic students, including Kurumu Kurono, a busty succubus and Yukari Sendo, an eleven-year-old witch. They join the school's Newspaper Club and wind up fighting a variety of students and teachers, who try to use their monstrous powers to bully or to control one or more of the group for their own selfish or destructive ends. On a club trip to the human world, they meet witch Ruby Tojo who tries to defend a field of sunflowers from being torn down by developers. They later meet Mizore Shirayuki, a snow fairy student who stalks Tsukune. A group of Monstrels students harass the club, causing Moka to transfuse too much of her blood into Tsukune, almost turning him into a ghoul. An evil group called theAnti-Schoolers threaten to ruin the school's festival and destroy the barrier between the human and monster world.
In Rosario+Vampire: Season II, Koko Shuzen, Moka's younger sister, enrolls; she, Ruby, and Mizore join the Newspaper Club. On an excursion to Mizore's homeland, they learn of a dangerous organization called Fairy Tale, which seeks to destroy the human world and must fight to keep the coexistence between humanity and monsters intact. Tsukune continues to train; the News Club visits the human world where they meet San Otonashi, a former club member, as they run into trouble with Fairy Tale's 7th Branch office. A Chinese transfer student, Fangfang Huang tries to recruit Tsukune to join his mafia family. Inner Moka spends a day at school, but when she is unable to be sealed, the News Club gang head to China to get the rosario fixed.
At Hong Kong, Tsukune and the gang learn the truth about Moka's identity, that she was infused with shinso (noble) blood by her mother Akasha Bloodriver who sacrifices herself to protect them from Alucard, the First Ancestor vampire. Moka's eldest sister Aqua infiltrates the Huang manor and captures Moka to bring to Fairy Tale, as she is the key to reviving Alucard. While his friends train their powers, Tsukune's body is reworked by Tohofuhai to handle the upcoming challenges.
Tsukune and the gang infiltrate Fairy Tale's headquarters, a sky fortress, but face opposition by their leader Gyokuro Shuzen, who sends the leaders of the various divisions after them. They eventually reach Moka, but must face her sisters Aqua and Kahlua. Gyokuro snatches Moka's rosario in order to control Alucard. The Masked King reveals himself to be a clone of Alucard's original self prior to assuming his monster form. He reveals that he has manipulated both Fairy Tale and its opposition to determine whether the rosario could control him, and then merges with his monster self, who goes on a rampage in Tokyo.
Outer Moka is mortally wounded, but Tsukune revives her by removing all his holy locks and transforming himself into a shinso vampire. They beat down Alucard, but he revives and reveals that he has hatched eggs in Japan's major cities. Tsukune's friends and allies, along with the two other Dark Lords, band together to fight Alucard and his clones. Tsukune puts Moka's rosario on Alucard, which awakens Akasha inside his monster body. Akasha tells Alucard to give up the fight, and they cast a self-disintegration spell. Now that the existence of monsters is known in the human world, coexistence is now even harder to achieve, however, Tsukune is confident that he and his friends can do it.
