In the mid-1950s, she read J. R. R. Tolkien's The Lord of the Rings, which had an enormous impact on her. But rather than making her want to follow in Tolkien's footsteps, it simply showed her what was possible with the fantasy genre.

From 1951 to 1961 she wrote five novels, which publishers rejected, because they seemed inaccessible. She also wrote poetry during this time, including Wild Angels (1975).

In 1953, while traveling to France aboard the Queen Mary, Le Guin met her Future husband, Historian Charles Le Guin. They married later that year in Paris. After marrying, Le Guin chose not to continue her doctoral studies of the poet Jean Lemaire de Belges.

The couple returned to the United States so that he could pursue his Ph.D. at Emory University. During this time, she worked as a secretary and taught French at the university level. Their first child, Elisabeth (1957), was born in Moscow, Idaho, where Charles taught. In 1958 the Le Guins moved to Portland, Oregon, where their daughter Caroline (1959) was born, and where they lived thereafter. Charles is Emeritus Professor of History at Portland State University. During this time, she continued to make time for writing in addition to maintaining her family life. In 1964, her third child, Theodore, was born.

Her earliest writings, some of which she adapted in Orsinian Tales and Malafrena, were non-fantastic stories set in the imaginary country of Orsinia. Searching for a way to express her interests, she returned to her early interest in science fiction; in the early 1960s her work began to be published regularly. One Orsinian Tale was published in the Summer 1961 issue of The Western Humanities Review and three of her stories appeared in 1962 and 1963 numbers of Fantastic Stories of Imagination, a monthly edited by Cele Goldsmith. Goldsmith also edited Amazing Stories, which ran two of Le Guin's stories in 1964, including the first "Hainish" story.

In 1964 the short story "The Word of Unbinding" was published. This was the first of the Earthsea fantasy series, which includes six books and eight short stories. The three linked young adult novels beginning with A Wizard of Earthsea (1968), The Tombs of Atuan (1970), and The Farthest Shore (1972), sometimes referred to as The Earthsea Trilogy, in later years would be joined by the books Tehanu, Tales from Earthsea and The Other Wind.

Le Guin received wide recognition for her novel The Left Hand of Darkness, which won the Hugo and Nebula awards in 1970. Her subsequent novel The Dispossessed made her the first person to win both the Hugo and Nebula Awards for Best Novel twice for the same two books.

Few of Le Guin's major works have been adapted for film or television. Her 1971 novel The Lathe of Heaven has been adapted twice: The first adaptation was made in 1979 by WNET Channel 13 in New York, with her own participation, and the second adaptation was made in 2002 by the A&E Network. In a 2008 interview, she said she considers the 1979 adaptation as "the only good adaptation to film" of her work to date.

Le Guin won dozens of annual "year's best" literary awards. For novels alone she won five Locus, four Nebula, two Hugo, and one World Fantasy Award. (The Dispossessed won the Locus, Nebula, and Hugo.) She also won those four awards in short fiction categories, although she turned down a Nebula award for her novelette The Diary of the Rose in protest at the Science Fiction Writers of America's treatment of Stanisław Lem. Her nineteen Locus Awards, voted by magazine subscribers, are more than any other Writer has received. Her third Earthsea novel, The Farthest Shore, won the 1973 National Book Award for Young People's Literature, and she was a finalist for ten Mythopoeic Awards, nine in Fantasy and one for Scholarship. Unlocking the Air and Other Stories was one of three finalists for the 1997 Pulitzer Prize for Fiction. She won the 2017 Hugo Award for Best Related Work for a collection of essays entitled Words Are My Matter: Writings About Life and Books, 2000–2016.

Recognizing her stature in the speculative fiction genre, Le Guin was the Professional Guest of Honor at the 1975 World Science Fiction Convention in Melbourne, Australia. That year she was also named the sixth Gandalf Award Grand Master of fantasy. The Science Fiction Research Association (SFRA) gave her its Pilgrim Award in 1989 for her "lifetime contributions to SF and fantasy scholarship". At the 1995 World Fantasy Convention she won the World Fantasy Award for Life Achievement, a judged recognition of outstanding Service to the fantasy field. The Science Fiction and Fantasy Hall of Fame inducted her in 2001, its sixth class of two deceased and two living Writers. The Science Fiction and Fantasy Writers of America made her its 20th Grand Master in 2003. In 2010, Le Guin was awarded the Lyman Tower Sargent Distinguished Scholar Award by the North American Society for Utopian Studies.

In later years, Le Guin worked in film and audio. She contributed to The Lathe of Heaven, a 1979 PBS film based on her novel of the same name. In 1985 she collaborated with avant-garde Composer David Bedford on the libretto of Rigel 9, a space opera. In May 1983 she delivered a well-received commencement address entitled "A Left-Handed Commencement Address" at Mills College, Oakland, California. "A Left-Handed Commencement Address" is included in her nonfiction collection Dancing at the Edge of the World.

In the early 1980s Animator and Director Hayao Miyazaki asked permission to create an animated adaptation of Earthsea. However, Le Guin, who was unfamiliar with his work and anime in general, turned down the offer. Years later, after seeing My Neighbor Totoro, she reconsidered her refusal, believing that if anyone should be allowed to direct an Earthsea film, it should be Hayao Miyazaki. The third and fourth Earthsea books were used as the basis of the 2006 animated film Tales from Earthsea (ゲド戦記, Gedo Senki). The film, however, was directed by Miyazaki's son, Gorō, rather than Hayao Miyazaki himself, which disappointed Le Guin. While she was positive about the aesthetic of the film, writing that "much of it was beautiful", she took great issue with its re-imagining of the moral sense of the books and greater focus on physical violence. "[E]vil has been comfortably externalized in a villain", Le Guin writes, "the wizard Kumo/Cob, who can simply be killed, thus solving all problems. In modern fantasy (literary or governmental), killing people is the usual solution to the so-called war between good and evil. My books are not conceived in terms of such a war, and offer no simple answers to simplistic questions."

Her speech "A Left-Handed Commencement Address", given in 1983 at Mills College, is listed as  No. 82 in American Rhetoric's Top 100 Speeches of the 20th Century (listed by rank).

In 1984, Le Guin was part of a group along with Ken Kesey, Brian Booth, and william Stafford that founded the Oregon Institute of Literary Arts, which is now known as Literary Arts in Portland.

In 1987, the CBC Radio anthology program Vanishing Point adapted The Dispossessed into a series of six 30-minute episodes, and at an unspecified date The Word for World Is Forest as a series of three 30-minute episodes.

Elizabeth McDowell states in her 1992 master's thesis that Le Guin "identif[ies] the present dominant socio-political American system as problematic and destructive to the health and life of the natural world, humanity, and their interrelations". This idea recurs in several of Le Guin's works, most notably The Left Hand of Darkness (1969), The Word for World Is Forest (1972), The Dispossessed (1974), The Eye of the Heron (1978), Always Coming Home (1985), and "Buffalo Gals, Won't You Come Out Tonight" (1987). All of these works center on ideas regarding socio-political organization and value-system experiments in both utopias and dystopias. As McDowell explains, "Although many of Le Guin's works are exercises in the fantastic imagination, they are equally exercises of the political imagination."

In 1995, Chicago's Lifeline Theatre presented its adaptation of The Left Hand of Darkness. Reviewer Jack Helbig at the Chicago Reader wrote that the "adaptation is intelligent and well crafted but ultimately unsatisfying", in large measure because it is extremely difficult to compress a complex 300-page novel into a two-hour stage presentation.

In April 2000 the U.S. Library of Congress made Le Guin a Living Legend in the "Writers and Artists" category for her significant contributions to America's cultural heritage. In 2002 she won a PEN/Malamud Award for "excellence in a body of short fiction". In 2004 she received two American Library Association honors for her lasting contributions: for young adult literature, the annual Margaret Edwards Award; for children's literature, selection to deliver the annual May Hill Arbuthnot Lecture. The annual Edwards Award recognizes one Writer and a particular body of work; the 2004 panel cited six works published from 1968 to 1990: A Wizard of Earthsea, The Tombs of Atuan, The Farthest Shore, and Tehanu (the first four Earthsea books), The Left Hand of Darkness and The Beginning Place. The panel said that Le Guin "has inspired four generations of young adults to read beautifully constructed language, visit fantasy worlds that inform them about their own lives, and think about their ideas that are neither easy nor inconsequential".

In 2004 the Sci Fi Channel adapted the first two books of the Earthsea trilogy as the miniseries Legend of Earthsea. Le Guin was highly critical of the adaptation, calling it a "far cry from the Earthsea I envisioned", objecting both to the use of white actors for her red, brown, or black-skinned characters, and to the way she was "cut out of the process".

Film-maker Arwen Curry began production on a documentary about Le Guin in 2009, filming "dozens" of hours of interviews with the author as well as many other Writers and artists who have been inspired by her. Curry launched a successful crowdfunding campaign to finish the documentary in early 2016 after winning a grant from the National Endowment for the Humanities.

Her novella, Paradises Lost, published in The Birthday of the World: and Other Stories, was adapted into an opera by the American Composer Stephen Andrew Taylor and Canadian librettist Marcia Johnson. The opera premiered April 26, 2012 at the Krannert Center for the Performing Arts on the campus of the University of Illinois.

In 2013, the Portland Playhouse and Hand2Mouth Theatre produced a stage adaptation of The Left Hand of Darkness, directed and adapted by Jonathan Walters, with text adapted by John Schmor. The play opened May 2, 2013, and ran until June 16, 2013, in Portland, Oregon.

In 2014, Le Guin was awarded the Medal for Distinguished Contribution to American Letters by the National Book Foundation, a lifetime achievement award. Her acceptance speech, which criticized Amazon as a "profiteer" and praised her fellow authors of fantasy and science fiction, was widely considered the highlight of the ceremony.

In 2015, the BBC commissioned radio adaptations of The Left Hand of Darkness and the first three Earthsea novels. The Left Hand of Darkness was aired as two hour-long episodes, and Earthsea as six half-hour episodes.

In early 2017 Le Guin's award winning novel The Left Hand of Darkness was picked up by Critical Content, a production company formerly known as Relativity Television, to be produced as a television limited series. Le Guin was to serve as a consulting Producer on the project.

Le Guin died on January 22, 2018, at her home in Portland, Oregon; her son stated that she had been in poor health for several months. Her New York Times obituary called her "the immensely popular author who brought literary depth and a tough-minded feminist sensibility to science fiction and fantasy with books like The Left Hand of Darkness and the Earthsea series".