"Rosario + Vampire" is a manga series set in a world where humans coexist with supernatural beings, though most humans remain unaware of their existence. The story centers on Tsukune Aono, an ordinary human who accidentally enrolls in Yokai Academy, a school for monsters disguised as humans. Initially unaware of the school's true nature, Tsukune quickly discovers that his classmates are vampires, witches, werewolves, and other mythical creatures. Despite being a human in a dangerous environment, Tsukune decides to stay, fearing expulsion would reveal his secret and put him at risk.

The narrative primarily revolves around Tsukune's relationships with his classmates, particularly Moka Akashiya, a beautiful and powerful vampire. Moka has two distinct personalities: her outer, sweet and gentle self, and her inner, more aggressive and dominant self, which emerges when her rosary, which suppresses her true power, is removed. Tsukune forms a close bond with Moka, and their relationship becomes a central focus of the story. Over time, Tsukune also befriends other female classmates, including Kurumu Kurono, a succubus; Yukari Sendo, a young witch; and Mizore Shirayuki, a yuki-onna (snow woman). Each of these characters develops feelings for Tsukune, creating a comedic and often dramatic love triangle.

As the series progresses, Tsukune and his friends face various challenges, including rival students, dangerous monsters, and sinister organizations seeking to exploit or destroy them. Tsukune's humanity becomes both a vulnerability and a source of strength, as he learns to navigate the complexities of the monster world. The story delves into themes of acceptance, identity, and the coexistence of humans and monsters, often exploring the moral ambiguities of both worlds.

The manga is divided into two parts: the first series, which focuses on episodic adventures and character development, and the second series, "Rosario + Vampire Season II," which introduces a more serialized plot with higher stakes. In the second series, Tsukune undergoes significant changes, including gaining supernatural abilities, which complicate his relationships and force him to confront the darker aspects of the monster world. The narrative builds toward a climactic confrontation with powerful antagonists, culminating in a resolution that ties together the series' central themes and character arcs.