Cherryh was born in 1942 in St. Louis, Missouri and raised primarily in Lawton, Oklahoma. She began writing stories at the age of ten when she became frustrated with the cancellation of her favorite TV show, Flash Gordon. In 1964, she received a Bachelor of Arts degree in Latin from the University of Oklahoma (Phi Beta Kappa), with academic specializations in archaeology, mythology, and the history of engineering. In 1965, she received a Master of Arts degree in classics from Johns Hopkins University in Baltimore, Maryland, where she was a Woodrow Wilson fellow.

After graduation, Cherry taught Latin, Ancient Greek, the classics, and ancient history at John Marshall High School in the Oklahoma City public school system. While her job was teaching Latin, her passion was the history, religion, and culture of Rome and Ancient Greece. During the summers, she would conduct student tours of the ancient ruins in England, France, Spain, and Italy. In her spare time, she would write, using the mythology of Rome and Greece as plots for her stories of the future. Cherryh did not follow the professional path typical of science fiction writers at the time, which was to first publish short stories in science fiction and fantasy magazines and then progress to novels. In fact, Cherryh did not consider writing short stories until after she had several novels published.

Instead, Cherryh wrote novels in her spare time away from teaching and submitted these manuscripts directly for publication. Initially, she met with little success. In fact, she was forced to re-write some of her early works when various publishers lost the manuscripts she submitted. Retyping from carbon copies of her manuscripts was cheaper than paying for photocopying, and, in effect, forced her to rewrite those lost manuscripts (using carbon paper to make at least one copy of a manuscript was standard practice until the advent of the personal computer). Her breakthrough came in 1975 when Donald A. Wollheim purchased both manuscripts she had submitted to DAW Books, Gate of Ivrel and Brothers of Earth. The two novels were published in 1976, Gate of Ivrel preceding Brothers of Earth by several months (although she had completed and submitted Brothers of Earth first). The books won her immediate recognition and the John W. Campbell Award for Best New Writer in 1977.

Although not all of her works have been published by DAW Books, during this early period, she developed a strong relationship with the Wollheim family and their publishing company, frequently traveling to New York City and staying with the Wollheims in their Queens family home. Other companies that have published her novels include Baen Books, HarperCollins, Warner Books, and Random House (under its Del Rey Books imprint). She published six additional novels in the late 1970s.

In 1979, her short story "Cassandra" won the Best Short Story Hugo, and she quit teaching to write full-time. She has since won the Hugo Award for Best Novel twice, first for Downbelow Station in 1982 and then again for Cyteen in 1989.

In addition to developing her own fictional universes, Cherryh has contributed to several shared world anthologies, including Thieves World, Heroes in Hell, Elfquest, Witch World, Magic in Ithkar, and the Merovingen Nights series, which she edited. Her writing has encompassed a variety of science fiction and fantasy subgenres and includes a few short works of non-fiction. Her books have been translated into Czech, Dutch, French, German, Hebrew, Hungarian, Italian, Japanese, Latvian, Lithuanian, Polish, Portuguese, Romanian, Russian, Slovak, Spanish and Swedish. She has also translated several published works of fiction from French into English.

She now lives near Spokane, Washington, with science fiction/fantasy author and artist Jane Fancher. She enjoys skating, traveling and regularly makes appearances at science fiction conventions.

Her brother David A. Cherry is a science fiction and fantasy artist.

Cherryh uses a writing technique she has variously labeled "very tight limited third person", "intense third person", and "intense internal" voice. In this approach, the only things the writer narrates are those that the viewpoint character specifically notices or thinks about. If a starship captain arrives at a space station, for example, the narration may not mention important features of the station with which the captain is already familiar, even though these things might be of interest to the reader, because the captain does not notice them or think about them due to their familiarity. This technique can offer a similar experience to that of reading the viewpoint character's mind...sometimes at great length...and thus it can resemble stream of consciousness narrative.

Because of her varied and prolific output, it is difficult to classify her writing as part of any single subgenre of science fiction and fantasy. She considers the two to be part of a unified whole, and opposes attempts to segregate writers and fans by increasingly specific subgenre definitions. Regarding this issue, she has written, "[I] don't like this specialization in which one side sniffs at the other as if they were some other species. No, no, no. We started out one creature. I don't care if 'they' have spots. We're still the same breed of cat."

Cherryh's works depict fictional worlds with great realism supported by her strong background in linguistics, history, archaeology, and psychology. In her introduction to Cherryh's first book, Andre Norton compared the effect of the work to Tolkien's: "Never since reading The Lord of the Rings have I been so caught up in any tale as I have been in Gate of Ivrel." Another reviewer commented, "Her blend of science and folklore gives the novels an intellectual depth comparable to Tolkien or Gene Wolfe". Cherryh creates believable alien cultures, species, and perspectives, causing the reader to reconsider basic assumptions about human nature. Her worlds have been praised as complex and realistic because she presents them through implication rather than explication. She describes the difficulties of translating/expressing concepts between differing languages. This is best demonstrated in both the Chanur and Foreigner series.

She has described the process she uses to create alien societies for her fiction as being akin to asking a series of questions, and letting the answers to these questions dictate various parameters of the alien culture. In her view, "culture is how biology responds to its environment and makes its living conditions better." Some of the issues she considers critical to consider in detailing an intelligent alien race include:

• The physical environment in which the species lives
• The location and nature of the race's dwellings, including the spatial relationships between those dwellings
• The species' diet, method(s) of obtaining and consuming food, and cultural practices regarding the preparation of meals and eating (if any)
• Processes which the aliens use to share knowledge
• Customs and ideas regarding death, dying, the treatment of the race's dead, and the afterlife (if any)
• Metaphysical issues related to self-definition and the aliens' concept of the universe they inhabit

Her protagonists often attempt to uphold existing social institutions and norms in the service of the greater good while the antagonists often attempt to exploit, subvert or radically alter the predominant social order for selfish gain. She uses the theme of the outsider finding his (or her) place in society and how individuals interact with The Other. A number of Cherryh's novels focus on military and political themes. An underlying theme of her work is an exploration of gender roles. Her characters reveal both strengths and weaknesses regardless of their gender, although her female protagonists are portrayed as especially capable and determined.

In addition, many of her male characters are mentally damaged in some manner, having been through a physical, emotional, or mental trauma, generally as a result of intentional abuse: Josh Talley in Downbelow Station was mind-wiped and sexually abused; Sandor in Merchanter's Luck had his entire family killed and often pushes the limits of exhaustion and the use of tranks for jumps; Ramey (also known as NG, or No Good) in Rimrunners was sent through jump without his tranks, as was Tully in the Chanur series. Paul Dekker, the protagonist in Heavy Time went crazy after witnessing the murder of his close female friend, and is further abused in the sequel Hellburner. Several characters, including the main character, Thomas, in Tripoint have been psychologically and physically abused. Justin in Cyteen was repeatedly drugged and psychologically violated.

Her career began with publication of her first books in 1976, Gate of Ivrel and Brothers of Earth. She has been prolific since that time, publishing over 60 novels, short-story compilations, with continuing production as her blog attests. Ms. Cherryh has received the Hugo and Locus Awards for some of her novels. Her novels are divided into various spheres, focusing mostly around the Alliance-Union universe, The Chanur Novels, the Foreigner universe, and her fantasy novels.