O’Brien is born in Limerick, County Limerick on December 3, 1897. Following the death of her mother when she is five years old, she becomes a boarder at Laurel Hill Convent. She graduates in English and French from the newly established University College Dublin, and she then moves to London, where she works as a teacher for a year.
In 1922–1923, O’Brien works as a governess in the Basque Country, in the north of Spain, where she begins to write fiction. Upon her return to England, she works at the Manchester Guardian. After the success of her play Distinguished Villa in 1926, she takes to full-time writing and is awarded both the 1931 James Tait Black Memorial Prize and the Hawthornden Prize for her debut novel Without My Cloak. O’Brien is best known for her 1934 novel The Ante-Room, her 1941 novel The Land of Spices, and the 1946 novel That Lady.
Many of O’Brien’s books deal with issues of female agency and sexuality in ways that are new and radical at the time. Her 1936 novel, Mary Lavelle, is banned in Ireland and Spain, while The Land of Spices is banned in Ireland upon publication. In addition to novels, she writes plays, film scripts, short stories, essays, copious journalism, two biographical studies, and two very personal travelogues. Throughout her life, she feels a particular affinity with Spain. While her experiences in the Basque Country inspire Mary Lavelle, she also writes a life of the Spanish mystic Teresa of Avila, and she uses the relationship between the Spanish king Philip II and Maria de Mendoza to write the anti-fascist novel That Lady.
O’Brien writes a political travelogue, Farewell Spain, to gather support for the leftist cause in the Spanish Civil War, and it has been argued that she is close to anarchism in the 1930s. A feminist, her novels promote gender equality and are mostly protagonised by young women yearning for independence. Several of her books include positive gay/lesbian characters. Her determination to encourage a greater understanding of sexual diversity makes her a pioneer in queer literary representation. She is very critical of conservatism in Ireland, and by spearheading a challenge to the Irish Censorship Act, she helps bring to an end the cultural restrictions of the 1930s and 40s in the country.
Kate O’Brien lives much of her life in England and died in Faversham, near Canterbury, on August 13, 1974.