Bowles could read at age 3 and was writing stories by age 4. Soon, he wrote surrealistic poetry and music. In 1922, at age 11, he bought his first book of poetry, Arthur Waley's A Hundred and Seventy Chinese Poems. At age 17, he had a poem, "Spire Song", accepted for publication in transition. This Paris-based literary journal served as a forum for leading proponents of modernism — Djuna Barnes, James Joyce, Paul Éluard, Gertrude Stein and others. Bowles' interest in music also dated from his childhood, when his Father bought a phonograph and classical records. (Bowles was interested in jazz, but such records were forbidden by his Father.) His family bought a piano, and the young Bowles studied musical theory, singing, and piano. When he was 15, he attended a performance of Stravinsky's The Firebird at Carnegie Hall, which made a profound impression: "Hearing The Firebird made me determined to continue improvising on the piano when my Father was out of the house, and to notate my own music with an increasing degree of knowing that I had happened upon a new and exciting mode of expression."

Bowles entered the University of Virginia in 1928, where his interests included T. S. Eliot's The Waste Land, Prokofiev, Duke Ellington, Gregorian chant, and blues. He also heard music by George Antheil and Henry Cowell. In April 1929, he dropped out without informing his parents, and sailed with a one-way ticket for Paris and no intention of returning – not, he said later, running away, but "running toward something, although I didn't know what at the time." Bowles spent the next months working for the Paris Herald Tribune and developing a friendship with Tristan Tzara. By July, he returned to New York and worked at Duttons Bookshop in Manhattan, where he began work on an unfinished book of fiction, Without Stopping (not to be confused with his later autobiography of the same title).

Critics have described his music, in contrast, "as full of light as the fiction [is] of dark...almost as if the Composer were a totally different person from the Writer." During the early 1930s, Bowles studied composition (intermittently) with Aaron Copland; his music from this period "is reminiscent of Satie and Poulenc." Returning to New York in the mid-30s, Bowles became one of the preeminent composers of American theater music, producing works for william Saroyan, Tennessee Williams, and others, "show[ing] exceptional skill and imagination in capturing the mood, emotion, and ambience of each play to which he was assigned." Bowles said that such incidental music allowed him to present "climaxless music, hypnotic music in one of the exact senses of the word, in that it makes its effect without the spectator being made aware of it." At the same time he continued to write concert music, assimilating some of the melodic, rhythmic, and other stylistic elements of African, Mexican, and Central American music.

Paul Bowles first studied music with Aaron Copland. In the fall of 1931, following an introduction from Copland, he entered the studio of Virgil Thomson.

In 1937, Bowles returned to New York. Over the next decade, he established a solid reputation as a Composer, collaborating with Orson Welles, Tennessee Williams, and others on music for stage productions, as well as orchestral pieces.

In 1938, he married Jane Auer, an author and Playwright. It was an unconventional marriage; each of their intimate relationships were with people of their own sex, but the couple maintained close personal ties with each other. Bowles has frequently been featured in anthologies as a gay Writer, but during his life, he always regarded such typecasting as both absurd and irrelevant. After a brief sojourn in France, the couple were prominent among the literary figures of New York throughout the 1940s. Paul Bowles also worked under Virgil Thomson, as a music critic at the New York Herald Tribune. His light opera The Wind Remains, based on a poem by Federico García Lorca, was performed in 1943 with choreography by Merce Cunningham and conducted by Leonard Bernstein. His translation of Jean-Paul Sartre's play Huis Clos ("No Exit"), directed by John Huston, won a Drama Critic's Award in 1943.

In 1945, Bowles began writing prose again, beginning with a few short stories including "A Distant Episode". His wife Jane, he said, was the main influence upon his taking up fiction as an adult, when she published her first novel Two Serious Ladies (1943).

In 1947, Paul Bowles received a contract for a novel from Doubleday; with the advance, he moved permanently to Tangier. Jane joined him there the next year. Bowles commented:

Bowles traveled alone into the Algerian Sahara to work on the novel. He later said, "I wrote in bed in hotels in the desert." He drew inspiration from personal experience, noting years later that, "Whatever one writes is in a sense autobiographical, of course. Not factually so, but poetically so." He titled the novel The Sheltering Sky, from a song, "Down Among the Sheltering Palms", which he had heard every summer as a child. It was first published by John Lehmann in England, in September 1949, after Doubleday rejected the manuscript.

During the late 1950s, Morocco achieved independence. With a grant from the Rockefeller Foundation and sponsorship from the US Library of Congress, Bowles spent the months of August to September 1959 traveling throughout Morocco with Christopher Wanklyn and Mohammed Larbi, recording traditional Moroccan music. From 1959–1961, Bowles recorded a wide variety of music from the different ethnic groups in Morocco, including the Sephardic Jewish communities of Meknes and Essaouira. The majority of these recordings are being transferred to the digital medium at George Blood Audio and Video in Philadelphia.

In 1952, Bowles bought the tiny island of Taprobane, off the coast of Ceylon (now Sri Lanka). There, he wrote much of his novel The Spider's House and returned to Tangier in the warmer months. He returned to Sri Lanka most winters.

Bowles set his third novel, The Spider's House (Random House, New York, November 1955), in Fez, immediately prior to Morocco's gaining independence and sovereignty in 1956) In it, he charted the relationships among three immigrants and a young Moroccan: John Stenham, Alain Moss, Lee Veyron, and Amar. Reviewers noted that the novel marked a departure from Bowles' earlier fiction in that it introduced a contemporary political theme, the conflict between Moroccan nationalism and French colonialism. The UK edition (Macdonald) was published in January 1957.

In 1957, Jane Bowles suffered a mild stroke, which marked the beginning of a long and painful decline in her health. Her condition preoccupied Paul Bowles until Jane's death in 1973.

Paul Bowles was a pioneer in the field of North African ethnomusicology, making field recordings from 1959 to 1961 of traditional Moroccan music for the US Library of Congress. The collection includes dance music, secular music, music for Ramadan and other festivals, and music for animistic rituals. Bowles realised that modern culture would inevitably change and influence the practice of traditional music, and he wanted to preserve some of it.

In the 1960s Bowles began translating and collecting stories from the oral tradition of native Moroccan storytellers. His most noteworthy collaborators included Mohammed Mrabet, Driss Ben Hamed Charhadi (Larbi Layachi), Mohamed Choukri, Abdeslam Boulaich, and Ahmed Yacoubi.

In the autumn of 1968, invited by friend Oliver Evans, Bowles was a visiting scholar for one semester at the English Department of the San Fernando Valley State College, (now California State University, Northridge. He taught "Advanced Narrative Writing and the Modern European Novel."

In 1970, Bowles and Daniel Halpern started the literary magazine, Antaeus, based in Tangier. It featured many new authors, such as Lee Prosser, as well as more established authors, such as Lawrence Ferlinghetti, Daniel Halpern, and others. Bowles' work was also published, including his story "Afternoon with Antaeus", some fragments of an unfinished novel by his wife Jane Bowles, along with excerpts from "The Summer House." Antaeus was not published until 1994.

After Jane Bowles' death, on 4 May 1973 in Málaga, Spain, Bowles continued to live in Tangier. He wrote regularly and received many visitors to his modest apartment.

Paul Bowles is considered one of the artists to have shaped 20th-century literature and music. In his "Introduction" to Bowles' Collected Stories (1979,) Gore Vidal ranked the short stories as "among the best ever written by an American", writing: "the floor to this ramshackle civilization that we have built cannot bear much longer our weight. It was Bowles's genius to suggest the horrors which lie beneath that floor, as fragile, in its way, as the sky that shelters us from a devouring vastness".

In the summers of 1980 and 1982, Bowles conducted writing workshops in Morocco, at the American School of Tangier (under the auspices of the School of Visual Arts in New York). These were considered successful. Among several students who have become successful authors are Rodrigo Rey Rosa, the 2004 Winner of the Miguel Ángel Asturias National Prize in Literature, and Mark Terrill. In addition, Bowles designated Rey Rosa as the literary heir of his and Jane Bowles' estates. In 1982 Bowles published Points in Time, subtitled Tales From Morocco, a collection of stories. Divided into eleven parts, the work consists of untitled story fragments, anecdotes, and travel narratives. These stories are not included in either The Stories of Paul Bowles (Ecco Press) or Collected Stories and Later Writings (The Library of America).

In 1985, Bowles published his translation of Jorge Luis Borges' short story, "The Circular Ruins". It was collected in a book of 16 stories, all translated by Bowles, called She Woke Me Up So I Killed Her. This Borges story had previously been published in translations by the three main Borges translators: Anthony Kerrigan, Anthony Bonner, and James E. Irby. Critics have noted the differences amongst these four translations. Bowles' version is in his typical prose style; it is readily distinguishable from the other three, which have a more conservative idiomatic form of translation.

In 1988, when Bowles was asked in an interview what his social life was like, he replied, "I don't know what a social life is... My social life is restricted to those who serve me and give me meals, and those who want to interview me." When asked in the same interview how he would summarize his achievement, he said, "I've written some books and some music. That's what I've achieved."

Bowles had a cameo appearance at the beginning and end of the film version of The Sheltering Sky (1990), directed by Bernardo Bertolucci. Bowles' music was overlooked and mostly forgotten for more than a generation, but in the 1990s, a new generation of American Musicians and Singers became interested in his work again. Art song enthusiasts savor what are described as "charming, witty pieces." In 1994, Bowles was visited and interviewed by Writer Paul Theroux, who featured him in his last chapter of his travel book, The Pillars of Hercules.

In 1995, Bowles made his final return to New York, invited to a "Paul Bowles Festival" at Lincoln Center celebrating his music; it was performed by Jonathan Sheffer leading the Eos Orchestra. A related symposium on Bowles' work and interview were held at the New School for Social Research. A Canadian documentary on his life, "Let It Come Down: The Life of Paul Bowles" won Best Documentary at the 27th Annual International Emmy Awards in New York City.

Bowles died of heart failure on November 18, 1999 at the Italian Hospital in Tangier, aged 88. He had been ill for some time with respiratory problems. His ashes were buried in Lakemont, New York, next to the graves of his parents and grandparents.

Paul Bowles was born in Jamaica, Queens, New York City as the only child of Rena (née Winnewisser) and Claude Dietz Bowles, a dentist. His childhood was materially comfortable, but his Father was a cold and domineering parent, opposed to any form of play or entertainment, and feared by both his son and wife. According to family legend, Claude had tried to kill his newborn son by leaving him exposed on a window-ledge during a snowstorm. The story may not be true, but Bowles believed it was and that it encapsulated his relationship with his Father. Warmth in his childhood was provided by his mother, who read Nathaniel Hawthorne and Edgar Allan Poe to him – it was to the latter that he later attributed his own Desire to write stories, such as "The Delicate Prey", "A Distant Episode", and "Pages from Cold Point"

The plot follows three Americans: Port, his wife Kit, and their friend, Tunner, as they journey through the Algerian desert, culminating in Port's death and Kit's descent into madness. The reviewer for TIME magazine commented that the ends visited upon the two main characters "seem appropriate but by no means tragic", but that "Bowles scores cleanly with his minor characters: Arab pimps and prostitutes, French officers in garrison towns, [and] a stupidly tiresome pair of tourists—mother & son." In The New York Times, Playwright and critic Tennessee Williams commented that the book was like a summer thunderstorm, "pulsing with interior flashes of fire". The book quickly rose to the New York Times best-seller list, going through three printings in two months.

Renewal of respect for Paul Bowles' music has led to several commercial recording projects. In 2016 the Invencia Piano Duo (Andrey Kasparov and Oksana Lutsyshyn), in collaboration with Naxos Records and its American Classics division, released two CDs of Bowles' complete piano works.

Volume one opens with pieces inspired by Latin American themes, evocative of the composer’s interest in the culture and his fluency in the Spanish language. The second of the two volumes closes with arrangements of Blue Mountain Ballads (1946), set for piano duet by Dr. Andrey Kasparov, and three Miscellaneous pieces, set for two pianos by the American piano duo of Arthur Gold and Robert Fizdale. The latter three arrangements were uncovered in the Gold and Fizdale Collection, held in the Peter Jay Sharp Special Collections, Lila Acheson Wallace Library, The Juilliard School. Dr. Kasparov reconstructed the original manuscripts which permitted these duets to be recorded for the very first time.