She returned to the UK to film Stephen Poliakoff's 1930s jazz drama series, Dancing on the Edge, which started on BBC2 in 2013. For her work, she won the Golden Globe for Golden Globe Award for Best Supporting Actress – Series, Miniseries or Television Film. In 2015, she co-starred with Drew Barrymore and Toni Collette in the film Miss You Already.

Bisset first appeared uncredited as a prospective model in the 1965 film The Knack ...and How to Get It, directed by Richard Lester.

She made her official debut the following year in Roman Polanski's Cul-de-sac (1966), credited as "Jackie Bisset". She had a tiny part as a Dancer in Drop Dead Darling (1966).

In 1967, Bisset had her first noticeable part in the Albert Finney/Audrey Hepburn vehicle Two for the Road, as a woman in whom Finney's character is romantically interested. It was made by 20th Century Fox.

She gained mainstream recognition in 1968 when she replaced Mia Farrow for the role of Norma MacIver in The Detective, opposite Frank Sinatra. The film was made at Fox, whose executives had been impressed by Bisset's performance in Two for the Road.

In 1969, Bisset had the star role in the sex comedy The First Time. In the same year she appeared in Secret World.

She had another star part in The Grasshopper (1970), which was little seen, and was in The Mephisto Waltz (1971) with Alan Alda.

Bisset had the lead in a comedy Stand Up and Be Counted (1972). More popular was The Life and Times of Judge Roy Bean (1972), where she played the daughter of Paul Newman's title character.

Bisset went to France to appear in François Truffaut's Day for Night (1973), where she earned the respect of European critics and moviegoers as a serious Actress. She stayed in that country to make Le Magnifique (1973) with Jean-Paul Belmondo, a hit in France but little seen in English-speaking countries.

Bisset was one of many stars in the British whodunnit Murder on the Orient Express (1974), an enormous success. In Britain she starred in the remake of The Spiral Staircase (1975).

Bisset went to Germany for End of the Game (1975) directed by Maximillian Schell. In Italy, she co-starred with Marcello Mastroianni in Luigi Comencini's The Sunday Woman in 1975.

Bisset returned to Hollywood to support Charles Bronson in St. Ives (1976).

In 1977, Bisset gained wide publicity in America with her movie The Deep. Swimming underwater wearing only a T-shirt for a top helped make the film a box office success, leading Producer Peter Guber to quip, "That T-shirt made me a rich man!" and led many to credit her with popularising the wet T-shirt contest. At the time, Newsweek declared her "the most beautiful film Actress of all time". About that time, a small Dutch-produced film Bisset had made some years earlier was re-released in the United States under the title Secrets. That movie featured the only extensive nude scenes of Bisset's career and the producers cashed in on her fame.

By 1978, she was a household name. In that year she earned a Golden Globe nomination for Best Actress (Comedy) for her performance in Who Is Killing the Great Chefs of Europe?, and starred opposite Anthony Quinn in The Greek Tycoon, playing a role based on Jackie Onassis.

After making Together? (1979) in Italy, she appeared in some all-star films, When Time Ran Out (1980), with Paul Newman, among others, and Inchon (1980) with Laurence Olivier. Both were big flops.

Bisset has appeared in many made-for-TV movies since the mid-1980s, starting with the cable adaptation of Anna Karenina with Christopher Reeve in 1985. One of her later TV movies, in 2003, was America's Prince: The John F. Kennedy Jr. Story, in which she portrayed Jacqueline Bouvier Kennedy Onassis. Bisset's other television work includes the Biblical epics Jesus (1999) and In the Beginning (2000), and the miniseries Joan of Arc, which earned her an Emmy nomination for Best Supporting Actress.

More popular was George Cukor's Rich and Famous (1981) with Candice Bergen, where Bisset also served as co-producer.

One of her well-known roles was in Class (1983), where she played Rob Lowe's attractive mother who has an affair with her son's prep school roommate (Andrew McCarthy).

Bisset made a wartime drama Forbidden (1984). For TV she played the title role in Anna Karenina (1985) and did an abortion drama, Choices (1986).

Bisset had the lead in some comedies: High Season (1987) and Scenes from the Class Struggle in Beverly Hills (1989), playing a lascivious suburban widow in the latter. She was Carré Otis' employer/educator in the controversial erotic thriller Wild Orchid (1990) with Mickey Rourke.

In 1996, Bisset was nominated for a César Award for her role in the French film La Cérémonie. She appeared in the 16th-century period drama Dangerous Beauty (1998) as Catherine McCormack's mother, a retired Venetian courtesan, and had the leading role in the 2001 independent feature The Sleepy Time Gal, which premiered on the Sundance Channel and was cited by the Village Voice in its annual survey of the year's best undistributed films. In 2005, she was seen in the Domino Harvey biographical film Domino with Keira Knightley, directed by Tony Scott, in which Bisset played a fictionalized version of Paulene Stone (renamed "Sophie Wynn") whom she actually knew from her time as a model in London.

In 2006, Bisset had a recurring role on the TV series Nip/Tuck as the ruthless extortionist James. She starred in the lead role of Boaz Yakin's Death in Love which premiered at the 2008 Sundance Film Festival. Later that year, she starred in the Hallmark television film An Old Fashioned Thanksgiving. She finished filming The Last Film Festival in 2010, which was the final screen appearance of Dennis Hopper.

Bisset has never married, though she has had lengthy romances with French-Canadian actor Michael Sarrazin, Moroccan real estate magnate Victor Drai, Russian dancer/actor Alexander Godunov, Swiss actor Vincent Pérez, and Turkish martial arts instructor Emin Boztepe. "I feel like I was married to them because I was very dedicated to them", she said in a 2008 interview. "But I also used to feel claustrophobic. Like many people who don't easily commit, I think I had a fear of being known; I was not sure there was anybody inside there."

In 2010, Bisset was awarded the Légion d'honneur insignia, with French President Nicolas Sarkozy calling her "a movie icon".

Bisset grew up in Tilehurst, near Reading in Berkshire, in a 17th-century country cottage, where she now lives part of the year She has a brother, Max. Her mother taught her to speak French fluently, and she was educated at the Lycée Français in London. She had taken ballet lessons as a child, and now began taking acting lessons while working as a fashion model to pay for them. When Bisset was a teenager, her mother was diagnosed with disseminating sclerosis.