"Release the Spyce" is set in the fictional city of Sorasaki, where a secret organization called Tsukikage operates to protect the city from crime and corruption. The organization is composed of female agents who enhance their physical abilities by consuming a special spice. The story centers on Momo Minamoto, a high school student who joins Tsukikage after being inspired by her upperclassman, Yuki Hanzōmon, who is also a seasoned agent. Momo trains under Yuki and gradually becomes more proficient in espionage, combat, and the use of the spice, which grants heightened senses and strength but must be used cautiously to avoid addiction.

The narrative unfolds as Momo and her fellow agents, including the skilled but aloof Goe Ishizue, the cheerful and tech-savvy Mei Yachiyo, and the disciplined and serious Fuu Sagami, undertake missions to thwart criminal organizations threatening Sorasaki. The primary antagonist is Moryo, a shadowy syndicate involved in illegal activities, including drug trafficking and human experimentation. As the series progresses, the agents uncover deeper layers of Moryo's operations, leading to high-stakes confrontations and personal challenges for the Tsukikage team.

Character dynamics play a significant role in the story, particularly the mentor-student relationship between Yuki and Momo, which evolves as Momo gains confidence and independence. The series balances action-packed sequences with moments of camaraderie and character development, highlighting the bonds between the agents as they navigate the dangers of their missions. Themes of trust, loyalty, and the moral complexities of espionage are explored as the characters confront both external threats and internal struggles. The plot builds toward a climactic showdown with Moryo, testing the resolve and abilities of the Tsukikage agents as they fight to protect their city.