Her first serializations at Shogakukan – the vampire fantasy The Poe Clan, the shōnen-ai (male–male romance) drama The Heart of Thomas, and the science fiction thriller They Were Eleven – were among the first works of shōjo manga to achieve mainstream critical and commercial success.

While Hagio primarily authors works in the science fiction, fantasy, and shōnen-ai genres, her manga explores a wide range of themes and subjects, including comedy, historical drama, and social and environmental issues.

She has been recognized with numerous awards both in Japan and internationally, including the Order of the Rising Sun, a Medal of Honor, and commendation as a Person of Cultural Merit.

[2] Hagio began to draw at an early age in her spare time, and attended private art lessons with her older sister.

[6] Contemporaneously, Hagio's editor assigned her to assist manga artist Keiko Takemiya, whose work had been published in Nakayoshi, COM, and Margaret.

[7] Shortly thereafter, Takemiya introduced Hagio to Junya Yamamoto [ja], an editor at Shogakukan and editor-in-chief of the manga magazine Bessatsu Shōjo Comic.

The Ōizumi Salon aimed to improve the quality and reputation of shōjo manga, a demographic which at the time was dismissed by critics as publishing frivolous stories for young children.

[14] Following a 1973 trip to Europe by Hagio, Masuyama, and Yamagishi, Takemiya announced that the Ōizumi Salon would cease, as she preferred to continue her career alone.

[16] Nonetheless, the innovation introduced to shōjo manga by the Year 24 Group significantly contributed to the development of the demographic, bringing it to what critics have described as its "golden age".

[8][9] In the wake of the critical and commercial success of The Rose of Versailles by Year 24 Group member Riyoko Ikeda, Hagio's editor Junya Yamamoto [ja] asked her to create a series of similar length and complexity for publication in the manga magazine Shūkan Shōjo Comic.

[17] The critical and commercial success of both The Poe Clan and The Heart of Thomas freed Hagio from most editorial constraints and allowed her to publish her previously rejected works of science fiction, a genre which at the time was perceived as inappropriate for female audiences and thus was effectively non-existent in shōjo manga.

Notable works include the crime thriller Mesh in 1980, the post-apocalyptic science fiction series Marginal from 1985 to 1987, the semi-autobiographical Iguana Girl in 1992, and A Cruel God Reigns from 1993 to 2001.

[13][21] To mark the fifteenth anniversary of Flowers in 2016, Hagio launched a revival of The Poe Clan in the magazine, publishing new chapters nearly forty years after the conclusion of the original series.

[24] In Hagio's manga specifically, interior monologues are often accompanied by symbolic motifs that extend beyond panel borders and overlap in a manner resembling a montage or a collage, creating a three-dimensional effect.

This is especially true of her short stories, which have depicted a variety of topics and genres including comedy, historical drama, and social and environmental issues.

[29] These early works nevertheless address dysfunctional family relationships, such as her one-shot Bianca (1970), a "gothic revenge plot" by a child against their parents and older authority figures.

[29] Familial drama nevertheless remains a common theme in her works, as expressed in stories that address topics of child abandonment, incestual rape, and abortion.

She has described a "sense of liberation"[33] that comes from writing male characters, as they allow her to express thoughts and concepts freely, in contrast to female protagonists who face the restrictions of a patriarchal society.

Dissatisfied with the draft, Hagio changed the protagonists to bishōnen; this aligned the story with the then-nascent genre of shōnen-ai, the precursor to modern boys' love (male–male romance manga).

Hagio's science fiction manga frequently explores topics relating to the place women in society, motherhood, and gender fluidity, taking particular inspiration from the works of Ursula K. Le Guin.