St. Clair was born in Hutchinson, Kansas. Her father, US Representative George A. Neeley, died when Margaret was seven, but left her mother well provided for. With no siblings, Margaret recalled her childhood as "rather a lonely and bookish one." When she was seventeen, she and her mother moved to California. In 1932, after graduating from the University of California, Berkeley, she married writer Eric St. Clair. In 1934 she earned a Master of Arts in Greek Classics. The St. Clairs lived in a hilltop house with a panoramic view in what is now El Sobrante, California, where Margaret gardened and bred and sold dachshund puppies.
In her rare autobiographical writings, St. Clair revealed few details of her personal life, but interviews with some who knew her indicate that she and her husband were well-traveled (including some visits to nudist colonies), were childless by choice, and in 1966 were initiated into Wicca by Raymond Buckland, taking the Craft names Froniga and Weyland. Eric St. Clair worked variously as a statistician, social worker, horticulturist, shopfitter, and a laboratory assistant in the University of California at Berkeley Physics Department; he also published numerous short stories and magazine articles and was "perhaps the leading American writer of children's stories about bears, having sold close to 100 of them."
The St. Clairs eventually moved from El Sobrante to a house on the coast near Point Arena, "where every window had an ocean view." Margaret survived her husband by several years. A lifelong supporter of the American Friends Service Committee, she spent her final years at Friends House in Santa Rosa, California. She died in 1995.
St. Clair wrote that she "first tried [her] hand at detective and mystery stories, and even the so-called 'quality' stories", before finding her niche writing fantasy and science fiction for pulp magazines. "Unlike most pulp writers, I have no special ambitions to make the pages of the slick magazines. I feel that the pulps at their best touch a genuine folk tradition and have a balladic quality which the slicks lack."
Beginning in the late 1940s, St. Clair wrote and published, by her own count, some 130 short stories. Her early output included the Oona and Jick series of eight stories published from 1947 to 1949, chronicling the comic misadventures of "housewife of the future" Oona and her devoted husband Jick. The stories were ostensibly set in an idealized future but cast a satirical look at post-war domestic life, with its focus on acquiring labor-saving household devices and "keeping up with the Joneses." St. Clair would later remark that the Oona and Jick stories "were not especially popular with fans, who were--then as now--a rather humorless bunch. The light tone of the stories seemed to offend readers and make them think I was making fun of them."
She was especially prolific in the 1950s, producing such acclaimed and much-reprinted stories as "The Man Who Sold Rope to the Gnoles" (1951), "Brightness Falls from the Air" (1951), "An Egg a Month from All Over" (1952), and "Horrer Howce" (1956). She occasionally drew inspiration from her education in Classics and her knowledge of Greek myth, as in "Mrs. Hawk" (1950), a modern update of the Circe myth, "The Bird" (1951), about a modern man's fateful encounter with the mythical phoenix, and "The Goddess on the Street Corner" (1953), in which a down-on-his-luck wino meets an equally vulnerable Aphrodite.
Beginning in 1950 with "The Listening Child", all of St. Clair's stories in The Magazine of Fantasy and Science Fiction appeared under the pseudonym Idris Seabright. The Seabright story "Personal Monster" appeared in the September 1955 issue immediately before the story "Too Many Bears" by a newcomer to the magazine, St. Clair's husband, Eric; in his introductory note to "Too Many Bears", editor Anthony Boucher quipped that Eric St. Clair "is enviably married to two of my favorite science fiction writers."
Three of her short stories were adapted for television. "Mrs. Hawk" was filmed as "The Remarkable Mrs. Hawk" for the 1961 season of Thriller, with Jo Van Fleet in the title role. "The Boy Who Predicted Earthquakes" (1950) and "Brenda" (1954) were filmed as segments of the 1971 season of Rod Serling's Night Gallery.
St. Clair wrote only a handful of stories in the mystery genre, but one of them, The Perfectionist (1946), was widely reprinted and translated, and served as the basis for the play A Dash of Bitters by Reginald Denham and Conrad Sutton Smith. She also wrote several pieces of fiction and satire for "gentlemen's magazines" including Gent and The Dude.
She used the Wilton Hazzard pseudonym, a general house name used in magazines published by Fiction House, for a story published in an issue of Planet Stories which already contained a story under her own name.
St. Clair also wrote eight novels, four of which were published in the Ace Double series.
Sign of the Labrys (1963) featured an overt early use of Wicca elements in fiction; St. Clair wrote that the book "was primarily inspired by Gerald Gardner's books on witchcraft." The editor of The Crystal Well called Sign of the Labrys "an occult classic," and in his review of the novel for Analog, P. Schuyler Miller declared that St. Clair was one of the most unappreciated writers in science fiction. St. Clair's research into witchcraft led to her friendship with Raymond Buckland, who recalled the St. Clairs as "absolutely wonderful people, very warm and loving."
From the outset of her career, St. Clair was aware of her unusual role as a woman writing in a male-dominated field. An article she wrote for Writer's Digest in 1947, about selling stories to the science fiction market, begins: "Why is science fiction fun to write? At first blush, it doesn't seem attractive, particularly for a woman." When the World Science Fiction Convention was held in Oakland in 1954, the Oakland Tribune highlighted St. Clair as a local author by asking her to provide a "menu of the future." The back cover of her 1963 paperback novel Sign of the Labrys declared in large capital letters, "Women Are Writing Science-Fiction!" and continued: "Women are closer to the primitive than men. They are conscious of the moon-pulls, the earth-tides. They possess a buried memory of humankind's obscure and ancient past which can emerge to uniquely color and flavor a novel. Such a woman is Margaret St. Clair...."
St. Clair's pioneering role as a woman writing science fiction was noted by Eric Leif Davin in his book Partners in Wonder: Women and the Birth of Science Fiction, 1926-1965.