A part-time high school teacher, Arata Kamishiro, returns to his family home following the death of his father. Years earlier, he had distanced himself from the family shrine, unwilling to inherit the responsibilities tied to it. Upon his return, he reunites with his young step-niece, Hina, who had grown distant during his absence. The normalcy of his homecoming is shattered when a monster, a God of Calamity, attacks the shrine. The blade his father left behind awakens, and a young woman named Hana appears to fight the creature, revealing herself to be a Hanamiko, a sacred maiden tasked with defeating these evil spirits.

Arata soon learns from Hana and others that his father was not merely a shrine priest but the leader of a group of these warrior maidens. They live and operate from the Night District Castle, a fortress where they reside while carrying out their mission. After the attack, Arata is taken there and informed that he is next in line to inherit his father's role. He is to become the new leader of this all-female team, much to his surprise. His primary motivation is to protect his niece Hina, who has become a Hanamiko herself. However, he quickly discovers that managing this group of unique and problematic young women is far more difficult than he could have imagined.

The world of Sakigake no Hanamiko is defined by the conflict between humanity and the Calamity Gods, entities that bring disaster. The Hanamiko are the warriors created to fight these beings. The maidens of the Night District Castle also serve a unique cultural role, entertaining visiting benevolent spirits through traditional arts such as dance, music, and conversation, similar to how geisha would entertain guests. This dual role of warrior and performer is central to their existence as flower shrine maidens, a title that references the famous geisha street, Hanamikoji.

The cast is centered on Arata Kamishiro, a reserved teacher nicknamed Buddha Kamishiro at school, who is determined not to abandon his family again and vows to be the new keeper of the shrine. Hina Kamishiro, his step-niece and only remaining relative, works as a shrine maiden and is also known as Hinagiku. The other four main Hanamiko each have distinct personalities and appearances. Inazuma has a tanned appearance and wears earrings; Gekka has light hair and wears a hairpin; Harutsubaki has short hair and often wears flowers in her hair; and Nazuna has a more mature appearance. Together, this group must balance their dangerous combat missions, the complicated dynamics of their shared living situation, and the growing romantic tension, all under the reluctant leadership of their new teacher-turned-chief.

The narrative follows Arata's struggle to earn the respect of the Hanamiko, unite them as an effective fighting force, and uncover the full truth behind his father's death and the origins of the Calamity Gods. The story, which began serialization in Kodansha's Magazine Pocket app, concluded with its 78th chapter, bringing Arata's journey as the leader of the flower shrine maidens to a close.