Schlesinger's acting career began in the 1950s and consisted of supporting roles in British films such as The Divided Heart and Oh... Rosalinda!!, and British television productions such as BBC Sunday Night Theatre, The Adventures of Robin Hood and The Vise. He began his directorial career in 1956 with the short documentary Sunday in the Park about London's Hyde Park. In 1958, Schlesinger created a documentary on Benjamin Britten and the Aldeburgh Festival for the BBC's Monitor TV programme, including rehearsals of the children's opera Noye's Fludde featuring a young Michael Crawford. In 1959, Schlesinger was credited as exterior or second unit Director on 23 episodes of the TV series The Four Just Men and four 30-minute episodes of the series Danger Man.

By the 1960s, he had virtually given up acting to concentrate on a directing career, and another of his earlier directorial efforts, the British Transport Films' documentary Terminus (1961), gained a Venice Film Festival Gold Lion and a British Academy Award. His first two fiction films, A Kind of Loving (1962) and Billy Liar (1963) were set in the North of England. A Kind of Loving won the Golden Bear award at the 12th Berlin International Film Festival in 1962. His third feature film, Darling (1965), tartly described the modern, urban way of life in London and was one of the first films about 'swinging London'. Schlesinger's next film was the period drama Far from the Madding Crowd (1967), an adaptation of Thomas Hardy's popular novel accentuated by beautiful English country locations. Both films (and Billy Liar) featured Julie Christie as the female lead.

Schlesinger also directed Timon of Athens (1965) for the Royal Shakespeare Company and the musical I and Albert (1972) at London's Piccadilly Theatre. From 1973, he was an associate Director of the Royal National Theatre, where he produced George Bernard Shaw's Heartbreak House (1975). He also directed several operas, beginning with Les contes d'Hoffmann (1980) and Der Rosenkavalier (1984), both at Covent Garden. Schlesinger also directed a party political broadcast for the Conservative Party in the general election of 1992, which featured Prime Minister John Major returning to Brixton in south London, where he had spent his teenage years, which highlighted his humble background, atypical for a Conservative Politician. Schlesinger admitted to having voted for all three main political parties in the UK at one time or another.

Schlesinger's next film, Midnight Cowboy (1969), was internationally acclaimed. A story of two hustlers living on the fringe in the bad side of New York City, it was Schlesinger's first film shot in the US, and it won Oscars for Best Director and Best Picture. During the 1970s, he made an array of films that were mainly about loners, losers and people outside the clean world, such as Sunday Bloody Sunday (1971), The Day of the Locust (1975), Marathon Man (1976) and Yanks (1979). Later, came the major box office and critical failure of Honky Tonk Freeway (1981), followed by films that attracted mixed responses from the public, and few dollars, althoughThe Falcon and the Snowman (1985) made money and Pacific Heights (1990) was a box-office hit. In Britain, he did better with films like Madame Sousatzka (1988) and Cold Comfort Farm (1995). Other later works include An Englishman Abroad (1983), the TV play A Question of Attribution (1991), The Innocent (1993) and The Next Best Thing (2000).

Schlesinger was made a Commander of the Order of the British Empire (CBE) for his services to film in 1970. In 2003, a Golden Palm Star on the Palm Springs, California Walk of Stars was dedicated to him.

Schlesinger underwent a quadruple heart bypass in 1998, before suffering a stroke in December 2000. He was taken off life support at Desert Regional Medical Center in Palm Springs on 24 July 2003, and he died early the following day at the age of 77. He was survived by his partner of over 30 years, Photographer Michael Childers. A memorial Service was held on 30 September 2003.