The world of Yozakura Quartet consists of two separate realms: one inhabited by humans and another by youkai. Though they largely resemble humans, youkai often possess animal-like features and a variety of supernatural powers. Normally confined to their own dimension, some youkai have crossed into the human world. To symbolize harmony and serve as a link between the two sides, a city was built within the protective barrier of seven enchanted trees, known as the Seven Pillars. This city, Sakurashin, houses both humans and youkai, with the peace between them upheld by the Hizumi Life Counseling Office.
The office is run by Akina Hiizumi, a teenager who inherited his family's ability called "tuning," which can permanently banish harmful youkai back to their own world. He is supported by a group of girls: Hime Yarizakura, the 16-year-old youkai mayor of the town; Ao Nanami, the local announcer and a telepath; and Kotoha Isone, a half-youkai capable of summoning any object simply by speaking its name.
As new inhabitants arrive and strange occurrences unfold, this quartet of guardians, along with their closest allies, must continue protecting Sakurashin and preserving the delicate balance of peace between humans and youkai.