The world of Yozakura Quartet consists of two distinct realms: one for humans and one for youkai. Although youkai generally appear human, they may possess animal-like physical traits and various special abilities. While youkai are typically confined to their own world, some have managed to enter the human realm. To symbolize peace and serve as a bridge between these two worlds, a city was built within the protective barrier of seven magical trees, known as the Seven Pillars. This city, Sakurashin, is inhabited by both humans and youkai, with the peace between them upheld by the Hizumi Life Counseling Office. The office is directed by Akina Hiizumi, a teenager who inherits his family's ability to perform “tuning,” a power that can permanently send harmful youkai back to their world. He is assisted by a group of girls, including Hime Yarizakura, the town’s 16-year-old youkai mayor; Ao Nanami, the town’s announcer and resident telepath; and Kotoha Isone, a half-youkai who can summon objects simply by stating their names. As new residents arrive and mysterious events unfold, this quartet of protectors and their closest friends must continue to guard Sakurashin and maintain the fragile peace between humans and youkai.