Moto Hagio made her professional debut in 1969 at the age of 20 with her short story "Lulu to Mimi" in Nakayoshi. Later, for Shogakukan Publishing, she produced a series of short stories for various magazines. Two years after her debut, she published Juichigatsu no Gimunajiumu (The November Gymnasium), a short story which dealt openly with love between two boys at a boarding school. The story was part of a larger movement by female manga artists at the time which pioneered a genre of girls' comics about love between young men. In 1974, Hagio developed this story into the longer Tōma no Shinzō (The Heart of Thomas). She was awarded the Shogakukan Manga Award in 1976 for her science fiction classic Juichinin Iru! (They Were Eleven) and her epic tale Poe no Ichizoku (The Poe Family). Moto Hagio had a role in the 2008 film Domomata no Shi (Death of Domomata).
Little of her work has been translated from Japanese. Following is a short list of those which have been translated:
A, A' and They Were Eleven have science fiction settings, and both They Were Eleven and X+Y include transgender elements. The science fiction aspects in particular have led to Hagio's work appealing to manga readers who do not generally like shōjo manga.
Moto Hagio did the character designs for Quintet's video game Illusion of Gaia.