"Yozakura Quartet ~Tsuki ni Naku~" is a supernatural action anime set in the fictional town of Sakurashin, where humans and supernatural beings coexist. The story revolves around the Himeyuri Agency, a group of young individuals tasked with maintaining peace and order in the town. The agency is led by Akina Hiizumi, a human with the unique ability to banish youkai (supernatural creatures) back to their world using a technique called "Tuning." Alongside him are Hime Yarizakura, the town's half-youkai mayor with superhuman strength; Ao Nanami, a telepathic catgirl; and Kotoha Isone, a human who can summon objects by chanting their names.

The narrative explores the challenges faced by the Himeyuri Agency as they confront various threats to the town's harmony. These threats often stem from rogue youkai, human conflicts, or external forces seeking to exploit the town's unique coexistence. A recurring antagonist is Kyousuke Kishi, a powerful youkai with a vendetta against Akina and his family. The series delves into the complexities of maintaining balance between humans and youkai, as well as the personal struggles and relationships of the main characters.

Themes of loyalty, identity, and the consequences of power are woven into the plot, as the characters navigate their roles in protecting Sakurashin. The story also highlights the bonds between the Himeyuri Agency members, emphasizing their teamwork and mutual trust. As the series progresses, deeper layers of the town's history and the origins of its supernatural elements are revealed, adding depth to the overarching narrative. The anime blends action, humor, and emotional moments, creating a dynamic and engaging storyline centered on the coexistence of two worlds.