Born at Wyberslegh Hall, High Lane, Cheshire in North West England, Isherwood spent his childhood in various towns where his father, a Lieutenant-Colonel in the British Army, was stationed. After his father was killed in the First World War, he settled with his mother in London and at Wyberslegh.

Isherwood attended preparatory school, St. Edmund's, Surrey, where he first met W. H. Auden. At Repton School he met his lifelong friend Edward Upward, with whom he wrote the extravagant "Mortmere" stories, of which one was published during his lifetime, a few others appeared after his death, and others he summarised in Lions and Shadows. He deliberately failed his tripos and left Corpus Christi College, Cambridge without a degree in 1925. For the next few years he lived with violinist André Mangeot, worked as secretary to Mangeot's string quartet and studied medicine. During this time he wrote a book of nonsense poems, People One Ought to Know, with illustrations by Mangeot's eleven-year-old son, Sylvain. It was not published until 1982.

In 1925 he was reintroduced to W. H. Auden and became Auden's literary mentor and partner in an intermittent, casual liaison. Auden sent his poems to Isherwood for comment and approval. Through Auden, Isherwood met Stephen Spender, with whom he later spent much time in Germany. His first novel, All the Conspirators, appeared in 1928. It was an anti-heroic story, written in a pastiche of many modernist novelists, about a young man who is defeated by his mother. In 1928—29 Isherwood studied medicine at King's College London, but gave up his studies after six months to join Auden for a few weeks in Berlin.

Rejecting his upper-middle class background and attracted to males, he remained in Berlin, the capital of the young Weimar Republic, drawn by its reputation for sexual freedom. There, he "fully indulged his taste for pretty youths. He went to Berlin in search of boys and found one called Heinz, who became his first great love." Commenting on John Henry Mackay's Der Puppenjunge (The Hustler), Isherwood wrote: "It gives a picture of the Berlin sexual underworld early in this century which I know, from my own experience, to be authentic."

In 1931 he met Jean Ross, the inspiration for his fictional character Sally Bowles. He also met Gerald Hamilton, the inspiration for the fictional Mr. Norris. In September 1931 the poet William Plomer introduced him to E. M. Forster. They became close and Forster served as his mentor. Isherwood's second novel, The Memorial (1932), was another story of conflict between mother and son, based closely on his own family history. During one of his return trips to London he worked with the director Berthold Viertel on the film Little Friend, an experience that became the basis of his novel Prater Violet (1945). He worked as a private tutor in Berlin and elsewhere while writing the novel Mr. Norris Changes Trains (1935) and a short novel called Goodbye to Berlin (1939) (often published together in a collection called The Berlin Stories). These works provided the inspiration for the play I Am a Camera (1951), the 1955 film I Am a Camera (both starring Julie Harris), the Broadway musical Cabaret (1966) and the film (1972) of the same name.

After leaving Berlin in 1933, he moved around Europe, and lived in Copenhagen, Sintra and elsewhere. He collaborated on three plays with Auden: The Dog Beneath the Skin (1935), The Ascent of F6 (1936), and On the Frontier (1939). Isherwood wrote a lightly fictionalised autobiographical account of his childhood and youth, Lions and Shadows (1938), using the title of an abandoned novel. Auden and Isherwood travelled to China in 1938 to gather material for their book on the Sino-Japanese War called Journey to a War (1939).

After visiting New York on their way back to Britain, Auden and Isherwood decided in January 1939 to emigrate to the United States. Their emigration happened just months before Britain entered the Second World War, and exposed them to charges that they lacked patriotism and commitment to the war effort. After a few months with Auden in New York, Isherwood settled in Hollywood, California.

During this period, Isherwood also befriended Truman Capote, an up-and-coming young writer who would be influenced by Isherwood's Berlin Stories, most specifically in the traces of the story "Sally Bowles" that surface in Capote's famed novella, Breakfast at Tiffany's. Ishwerwood also met Gerald Heard, the mystic-historian who founded his own monastery at Trabuco Canyon that was eventually gifted to the Vedanta Society of Southern California. Through Heard, who was the first to discover Swami Prabhavananda and Vedanta, Isherwood joined an extraordinary band of mystic explorers that included Aldous Huxley, Bertrand Russell, Chris Wood (Heard's lifelong friend), John Yale and J. Krishnamurti. He embraced Vedanta, and, together with Swami Prabhavananda, he produced several Hindu scriptural translations, Vedanta essays, the biography Ramakrishna and His Disciples, novels, all imbued with the themes and character of Vedanta and the Upanishadic quest. Through Huxley, Isherwood befriended the Russian composer Igor Stravinsky.

A chance encounter in a Los Angeles bookstore with the fantasy writer Ray Bradbury led to a favourable review of The Martian Chronicles, which boosted Bradbury's career and helped to form a friendship between the two men.

Isherwood considered becoming an American citizen in 1945 but balked at taking an oath that included the statement that he would defend the country. The next year he applied for citizenship and answered questions honestly, saying he would accept non-combatant duties like loading ships with food. The fact that he had volunteered for service with the Medical Corps helped as well. At the naturalization ceremony, he found he was required to swear to defend the nation and decided to take the oath since he had already stated his objections and reservations. He became an American citizen on November 8, 1946.

He began living with the photographer William (Bill) Caskey. In 1947 the two travelled to South America. Isherwood wrote the prose and Caskey took the photographs for a 1949 book about their journey, The Condor and the Cows. On Valentine's Day 1953, at the age of 48, he met teen-aged Don Bachardy among a group of friends on the beach at Santa Monica. Reports of Bachardy's age at the time vary, but Bachardy later said "at the time I was, probably, 16." Despite the age difference, this meeting began a partnership that, though interrupted by affairs and separations, continued until the end of Isherwood's life. During the early months of their affair, Isherwood finished–and Bachardy typed–the novel on which he had worked for some years, The World in the Evening (1954). Isherwood also taught a course on modern English literature at Los Angeles State College (now California State University, Los Angeles) for several years during the 1950s and early 1960s.

The more than 30-year age difference between Isherwood and Bachardy raised eyebrows at the time, with Bachardy, in his own words, "regarded as a sort of child prostitute", but the two became a well-known and well-established couple in Southern Californian society with many Hollywood friends.

Down There on a Visit, a novel published in 1962, comprised four related stories that overlap the period covered in his Berlin stories. In the opinion of many reviewers, Isherwood's finest achievement was his 1964 novel A Single Man, that depicted a day in the life of George, a middle-aged, gay Englishman who is a professor at a Los Angeles university. During 1964 Isherwood collaborated with American writer Terry Southern on the screenplay for the Tony Richardson film adaptation of The Loved One, Evelyn Waugh's caustic satire on the American funeral industry.

Isherwood and Bachardy lived together in Santa Monica for the rest of Isherwood's life. Bachardy became a successful draughtsman with an independent reputation, and his portraits of the dying Isherwood became well-known after Isherwood's death. At the age of 81, Isherwood died in 1986 in Santa Monica, California from prostate cancer. His body was donated to medical science, specifically to the UCLA Medical School.

The house in the Schöneberg district of Berlin where Isherwood lived bears a plaque memorializing his stay there between 1929 and 1933.

The 2008 film A Love Story chronicled Isherwood and Bachardy's lifelong relationship.

A Single Man was adapted into a film of the same name in 2009.

In 2010 Isherwood's autobiography, Christopher and His Kind, is to be adapted into a television film by the BBC, starring Matt Smith as Christopher Isherwood and directed by Geoffrey Sax.

Vedanta and the West was the official publication of the Vedanta Society of Southern California. It offered essays by many of the leading intellectuals of the time and had contributions from Aldous Huxley, Gerald Heard, Alan Watts, J. Krishnamurti, W. Somerset Maugham, and many others.

Isherwood was Managing Editor from 1943 until 1945. Together with Huxley and Heard, he served on the Editorial Advisory Board from 1951 until 1962.

Isherwood wrote the following articles that appeared in Vedanta and the West:

• Vivekananda and Sarah Bernhardt — 1943
• On Translating the Gita — 1944
• Hypothesis and Belief — 1944
• The Gita and War — 1944
• What is Vedanta? — 1944
• Ramakrishna and Vivekananda — 1945
• The Problem of the Religious Novel — 1946
• Religion Without Prayers — 1946
• Foreword to a Man of Boys — 1950
• An Introduction — 1951
• What Vedanta Means to Me — 1951
• Who Is Ramakrishna? — 1957
• Ramakrishna and the Future — 1958
• The Home of Ramakrishna — 1958
• Ramakrishna: A First Chapter — 1959
• The Birth of Ramakrishna — 1959
• The Boyhood of Ramakrishna — 1959
• How Ramakrishna Came to Dakshineswar — 1959
• Early Days at Dakshineswar — 1959
• The Vision of Kali — 1960
• The Marriage of Ramakrishna — 1960
• The Coming of the Bhariravi — 1960
• Some Visitors to Dakshineswar — 1960
• Tota Puri — 1960
• The Writer and Vedanta — 1961
• Mathur — 1961
• Sarada and Chandra — 1962
• Keshab Sen — 1962
• The Coming of the Disciples — 1962
• Introduction to Vivekananda — 1962
• Naren — 1963
• The Training of Naren — 1963
• An Approach to Vedanta — 1963
• The Young Monks — 1963
• Some Great Devotees — 1963
• The Gospel of Sri Ramakrishna — 1963
• The Last Year — 1964
• The Story Continues — 1964
• Letters of Swami Vivekananda — 1968
• Essentials of Vedanta — 1969

• All the Conspirators (1928; new edition 1957 with new foreword)
• The Memorial (1932)
• Mr. Norris Changes Trains (1935; U.S. edition titled The Last of Mr. Norris)
• The Dog Beneath the Skin (1935, with W. H. Auden)
• The Ascent of F6 (1937, with W.H. Auden)
• Sally Bowles (1937; later included in Goodbye to Berlin)
• On the Frontier (1938, with W.H. Auden)
• Lions and Shadows (1938, autobiography)
• Goodbye to Berlin (1939)
• Journey to a War (1939, with W.H. Auden)
• Prater Violet (1945)
• The Berlin Stories (1945; contains Mr. Norris Changes Trains and Goodbye to Berlin; reissued as The Berlin of Sally Bowles, 1975)
• The Condor and the Cows (1949, South-American travel diary)
• What Vedanta Means to Me (1951, pamphlet)
• The World in the Evening (1954)
• Down There on a Visit (1962)
• An Approach to Vedanta (1963)
• A Single Man (1964)
• Ramakrishna and His Disciples (1965)
• Exhumations (1966; journalism and stories)
• A Meeting by the River (1967)
• Essentials of Vedanta (1969)
• Kathleen and Frank (1971, about Isherwood's parents)
• Frankenstein: The True Story (1973, with Don Bachardy; based on their 1973 filmscript)
• Christopher and His Kind (1976, autobiography)
• My Guru and His Disciple (1980)
• October (1980, with Don Bachardy)
• The Mortmere Stories (with Edward Upward) (1994)
• Where Joy Resides: An Isherwood Reader (1989; Don Bachardy and James P. White, eds.)
• Diaries: 1939—1960, Katherine Bucknell, ed. (1996)
• A Fable (1997) originally co-written with Aldous Huxley
• A Meeting by the River (New edition, Minneapolis: University of Minnesota Press, 1999)
• Down There on a Visit (New edition, Minneapolis: University of Minnesota Press], 1999)
• The Memorial (New edition, Minneapolis: University of Minnesota Press, 1999)
• The World in the Evening (New edition, Minneapolis: University of Minnesota Press, 1999)
• Lost Years: A Memoir 1945—1951, Katherine Bucknell, ed. (2000)
• Lions and Shadows (Minneapolis: University of Minnesota Press, 2000)
• Christopher and His Kind (New edition, Minneapolis: University of Minnesota Press, 2001)
• My Guru and His Disciple (New edition, Minneapolis: University of Minnesota Press, 2001)
• Prater Violet (New edition, Minneapolis: University of Minnesota Press, 2001)
• A Single Man (New edition, Minneapolis: University of Minnesota Press, 2001)
• The Condor and the Cows (New edition with foreword by Jeffrey Meyers, Minneapolis: University of Minnesota Press, 2003)
• Where Joy Resides (New edition with introduction by Gore Vidal, Minneapolis: University of Minnesota Press, 2003)
• Kathleen and Christopher, Lisa Colletta, ed. (Letters to his mother, Minneapolis: University of Minnesota Press], 2005)
• Isherwood on Writing University of Minnesota Press, 2007)

Translations:

• Charles Baudelaire, Intimate Journals (1930; revised edition 1947)
• The Song of God: Bhagavad-Gita (with Swami Prabhavananda, 1944)
• Shankara's Crest-Jewel of Discrimination (with Swami Prabhavananda, 1947)
• How to Know God: The Yoga Aphorisms of Patanjali (with Swami Prabhavananda, 1953)