Paul Emil Breitenfeld was born in San Francisco on November 25, 1924, the son of Emil Breitenfeld, a pianist, organist and arranger who accompanied silent films, and Shirley King. His mother's mental health problems sent him in 1933 to live with relatives in New Rochelle, New York, for nearly five years. Back in San Francisco he took up the clarinet at twelve, played through San Francisco Polytechnic High School, where he co-edited the school newspaper, and went on to San Francisco State College as an English major. In college he began playing alto saxophone, drawn to the records of Lester Young and Charlie Parker. Drafted in his first year, he spent three years in an Army band stationed in San Francisco and was never called to combat. After his discharge he legally changed his surname to Desmond in 1946; his biographer Doug Ramsey relays a friend's account that he took it from the singer Johnny Desmond, whom the two had been listening to in 1942.

He had met Dave Brubeck in 1944, when Brubeck auditioned for the 253rd Army band, to which Desmond belonged; Brubeck was then sent overseas. After the war Desmond worked around the Bay Area as a sideman, played occasionally for Brubeck at the Geary Cellar, and for several weeks led a combo that included Brubeck at the Band Box in Redwood City. A falling-out followed when Desmond resigned from the Band Box job and Brubeck was shut out of taking over the residency. In 1950 Desmond toured for several months with Jack Fina's band, then heard Brubeck's trio on the radio and returned to California to mend things. Brubeck relented, and the two drew up a contract, signed only by Brubeck, that kept Brubeck as leader, barred him from firing Desmond, and gave Desmond twenty percent of the profits. The Dave Brubeck Quartet that resulted lasted from 1951 to December 1967.

The quartet built its audience on college campuses, and Jazz at Oberlin (recorded March 1953 at Oberlin College) and Jazz at the College of the Pacific (December 14, 1953) became early landmarks. A 1954 Time magazine story put Brubeck on the cover. Drummer Joe Morello joined in late 1956 on Desmond's recommendation, and bassist Eugene Wright came aboard in 1958 for the State Department tour of Europe and Asia, completing the lineup that lasted until the end. Morello's solo features caused friction with Desmond for years, and the two later reconciled and became close friends. In 1959, with the quartet planning Time Out, Morello asked for a showpiece in 5/4 time; Brubeck handed the job to Desmond, who wrote two melodies that Brubeck arranged into "Take Five." A June 25, 1959 attempt collapsed after more than twenty tries, and the quartet got the album take in two passes on July 1. Desmond thought of it as a throwaway. Issued as a promotional single in September 1959, it became a sleeper hit in 1961, reaching number 25 on the Billboard Hot 100 and number 6 in the United Kingdom, and it was the first jazz single to sell a million copies.

Desmond made his first records as a leader for Fantasy in 1954 and 1956 (the second featuring the mellophonist Don Elliott), recorded a quartet date with Gerry Mulligan for Verve in August 1957, and in September 1959 cut First Place Again for Warner Bros. with Jim Hall, Percy Heath and Connie Kay. At RCA Victor, with producer George Avakian, he made six albums: Desmond Blue with strings (sessions in 1961), Two of a Mind with Mulligan (1962), and four small-group albums built around Hall, Take Ten (1963), Bossa Antigua (1965), Glad to Be Unhappy (1965) and Easy Living (1966). The title piece of Take Ten, a 5/4 original in the manner of "Take Five," was the start of his bossa nova period, and the album's cover is by Andy Warhol.

When the quartet broke up in 1967 Desmond turned to Creed Taylor's CTI label, recording Summertime (sessions from October to December 1968) and From the Hot Afternoon (1969) with arrangements by Don Sebesky, and Bridge Over Troubled Water (1969) with Herbie Hancock and Ron Carter. Skylark (1973) added Jack DeJohnette, Bob James and the guitarist Gábor Szabó. After a stretch of inactivity, Hall brought him to the Half Note in New York in 1971, and that December Desmond played a Christmas concert at Town Hall with the Modern Jazz Quartet. He guested on Chet Baker's CTI albums and appeared on Hall's Concierto (1975). Through Hall he met the Canadian guitarist Ed Bickert; the two worked Toronto clubs in 1974 and 1975, and Bickert was the guitarist on Pure Desmond (September 1974) and on the Bourbon Street quartet recordings of 1975 with bassist Don Thompson and drummer Jerry Fuller, issued as Live (1976), Paul Desmond (1978) and Like Someone in Love (1992), and gathered in 2020 as Mosaic's The Complete 1975 Toronto Recordings.

Desmond also came back to Brubeck. Concerts in Paris, Rotterdam and Berlin in 1972 with Brubeck and Gerry Mulligan produced We're All Together Again for the First Time, the two men made the duo album 1975: The Duets, and in 1976 they played twenty-five shows in twenty-five nights across the United States by bus. The reunion tours of the 1970s included Two Generations of Brubeck, with Brubeck's sons in the group. His last concert with Brubeck came in February 1977 in New York, with few in the audience aware how ill he was. He passed away of lung cancer in New York City on May 30, 1977, at age 52. His will directed the royalties from "Take Five" to the American Red Cross, and he left his saxophone to Brubeck's son Michael. Ramsey's biography, Take Five: The Public and Private Lives of Paul Desmond, appeared in 2005.

Desmond's alto tone was light, airy and dry, which he likened to a dry martini, and he built his sound on Lester Young and Charlie Parker without copying Parker's fast bebop vocabulary; Ken Dryden, reviewing Ramsey's biography, counted him among the early-1950s saxophonists who chose a personal sound over Parker's furious licks. Critics tie his lyricism to Lee Konitz, whom Desmond counted as an influence, and place him in the West Coast cool school. His solos are praised for their logical construction, for easy access to the altissimo register, and for an improvised counterpoint heard at its best on his two albums with Gerry Mulligan. Much of the classic Brubeck quartet's appeal lay in the contrast between his floating alto and the leader's heavier, polytonal piano. He played a Selmer Super Balanced Action alto from about 1951 with a hard-rubber M. C. Gregory mouthpiece. Younger players have named him as a model, among them Anthony Braxton, who cites Desmond among his formative influences, and the Japanese altoist Kohsuke Mine, whose tone formed partly around Desmond's.