Asumi Kamogawa is a small, 14-year-old girl with a burning passion for the cosmos, especially the stars. Since her early childhood, she has been learning about space from a man she calls "Lion-san," a wise and friendly ghost wearing a giant lion head. Despite a rough family dynamic, Asumi decides to enroll in the Tokyo Space School.

Asumi soon makes a group of friends at school: Shinnosuke Fuchuuya, Asumi's childhood friend with glasses and somewhat brutal honesty; Kei Oumi, a very friendly girl who was inspired by Neil Armstrong's pictures of the first lunar landing; Marika Ukita, an unsociable yet beautiful girl with some secrets of her own; and Shuu Suzuki, a bold yet intelligent boy with a very laidback outlook.

Set in an alternate future where Japan's first man-made rocket crashed in 2010, Futatsu no Spica is a coming-of-age story revolving around these young high schoolers and their path toward the stars.