Titled Coming of the Seraphim in the early stages of its development, Angel Sanctuary was inspired by the Japanese fantasy novel Nocturne and was originally slated to be only ten chapters long, which led Yuki to worry about being able to properly end the story.

Angel Sanctuary made cultural references to various mythologies, including Greek and Norse, as well as to real-world people, music, literature, and places.

The OVA received more mixed reviews from critics, who were generally divided on whether they enjoyed it as an introduction to the events of the manga or found its content objectionable due to the sibling incest.

At the conclusion of the revolt, she sealed away her younger twin brother, Inorganic Angel Rosiel, within the Earth, emotionally unable to fulfill his request to be killed before he became insane and destructive.

Captured and branded a fallen angel, Alexiel was punished by having her body frozen and her soul endlessly reincarnated as a human whose life is full of misery.

While Rosiel is freed by his subordinate Katan, Setsuna finds his life and Sara's endangered by various attempts to awaken Alexiel's dormant soul within him.

Sara eventually dies protecting him from one of Rosiel's subordinates, and devastated, Setsuna awakens Alexiel's soul, causing widespread damage.

Awakening in her own body with Setsuna's help, Alexiel reveals to him that she had always loved him: because he had been born the opposite of his healthy sister, she bargained with God to save his life in exchange for her imprisonment, from which she later escaped with Lucifer, and an agreement to never show him any compassion.

[5] Sara, originally named Sana, was the first character designed, while the first episode of the manga imagined was one in which the protagonist's love interest "was actually a living angel".

[5] For the conclusion, she originally had planned to use a tragic ending, but decided against it in favor of a happy one, because she thought that it would be too upsetting for the fans to read after twenty volumes.

[6]: p.215 When Angel Sanctuary was adapted into an audio drama series, Yuki participated in selecting voice actors; around two to three auditioned for each role.

Editing the already finished script was the most difficult aspect of the adaptation for her, as time and space constraints resulted in the elimination of some scenes and she felt that sometimes a character's personality would be changed.

Greek mythology features prominently,[9] with allusions to the Orpheus' descent to the underworld,[8]: pp.76–82  the mythical location Hades,[9] Pandora's box,[10] and Prometheus.

[15] The Goth subculture in Tokyo, Japan, and rock bands with androgynous musicians influenced the clothing of the angels and demons in the series.

[13] References to literature appeared in the series, such as Lewis Carroll's children's novel Alice's Adventures in Wonderland[9] and the Brothers Grimm fairy tale "Rapunzel".

[3]: p.57  Jason Thompson wrote that Angel Sanctuary's portrayal of incest adhered to the "classical tormented sense" which results in unfavorable consequences for the involved characters, including "guilt, madness, and the punishment of heaven".

She wondered if it was possible for the natural world to coexist with science, despite continual, considerable environmental damage as a result of human innovations, and reflected that in the titles of Rosiel and Alexiel, the Inorganic and Organic Angels.

[24] Angel Sanctuary has been translated into a variety of languages, among them Chinese,[26] German,[27] Italian,[28] Polish,[29] Hungarian,[30] French,[31] Russian,[32] and Spanish.

[33] A sequel manga written by Yuki, titled Angel Sanctuary: Tokyo Chronos, began serialization in Hakusensha's Hana Yume Ai web magazine on 20 April 2022.

[47][48] Directed by Kiyoko Sayama and produced by Bandai Visual, Lantis, and Hal Film Maker, the Angel Sanctuary OVA consisted of three episodes: "Encounter", "Awakening", and "Regeneration".

[12]: p.12  Yuki's artwork received praise as detailed,[2][62] "breath-taking",[63] "absorbing",[18] and "beautiful",[2] though one reviewer found the art "overcrowded" and had difficulty distinguishing between the male and female characters.

[62] Liann Cooper of Anime News Network commented that the story of Angel Sanctuary was well written, despite the inclusion of shock factors, with enough plot twists to hold the attention of the reader while staying focused on the main narrative.

[66] Thompson wrote that the plot was difficult to follow because of the page layouts, the large cast of androgynous characters, and the dense world building.