She began her film career in 1965 and first came to prominence in 1968 with roles in The Detective, Bullitt, and The Sweet Ride, for which she received a Golden Globe nomination as Most Promising Newcomer.

In the 1970s, she starred in Airport (1970), The Mephisto Waltz (1971), Day for Night (1973), which won the Academy Award for Best Foreign Language Film, Le Magnifique (1973), Murder on the Orient Express (1974), St. Ives (1976), The Deep (1977), The Greek Tycoon (1978) and Who Is Killing the Great Chefs of Europe?

[10] Fox cast Bisset in her first lead part in The Cape Town Affair, opposite a then-unknown James Brolin, filmed in South Africa on a low budget.

In 1970, Bisset was one of many stars in the disaster film Airport; her role was that of a pregnant stewardess carrying Dean Martin's love child.

She reteamed with real-life boyfriend Michael Sarrazin for the romantic drama Believe in Me, in which she played a drug addict, and had the lead in the comedy Stand Up and Be Counted (1972).

A marketing strategy based around Bisset appearing in some scenes underwater wearing only a white T-shirt for a top helped make the film a box-office success.

"[14] Many credit her with popularising wet T-shirt contests,[15] but Bisset herself was disappointed that the marketing of her translucent costume detracted from the film's technical achievements.

She earned a Golden Globe nomination that year as Best Actress – Motion Picture Comedy for her performance opposite George Segal in Who Is Killing the Great Chefs of Europe?, and starred with Anthony Quinn in The Greek Tycoon, playing a role based on Jackie Onassis.

Bisset appeared in some all-star films: When Time Ran Out (1980), starring alongside Paul Newman and William Holden, and Inchon (1981), with Ben Gazzara.

[17] One of her best-known roles came in the coming-of-age comedy Class (1983), as a married woman having an affair with her son's (Rob Lowe) prep school roommate (Andrew McCarthy).

She also had the lead in some comedies: High Season (1987) and Scenes from the Class Struggle in Beverly Hills (1989), taking over for Faye Dunaway due to scheduling conflicts.

(1991), a biopic of Italian composer Gioachino Rossini; with Martin Sheen for a Paris-set TV movie called The Maid (1991); with Elliott Gould in the Dutch miniseries Hoffman's honger (1993); with Jean-Hugues Anglade in the French language film Les marmottes (1993); and with one of Japan's top stars, Masaya Kato in the Australian TV film Crimebroker (1993).

[21] She did a couple of period pieces, playing a spinster in 1890s New York in Linda Yellen's End of Summer (1997), and a retired courtesan in 16th-century Venice in Dangerous Beauty (1998) with Catherine McCormack.

In 1999, Bisset appeared in two high-calibre television projects, playing the Virgin Mary in Jesus and Isabelle d'Arc in Joan of Arc, opposite Jeremy Sisto and Leelee Sobieski in the respective titular roles.

[22] Let the Devil Wear Black (1999) was an independent film featuring Bisset in an ensemble cast, loosely retelling Shakespeare's Hamlet in modern-day Los Angeles.

She had the leading role in Christopher Münch's The Sleepy Time Gal (2001), in which she gave an understated portrayal of a terminally ill woman trying to put her life in order.

Co-starring Nick Stahl, Seymour Cassel and Amy Madigan, The Sleepy Time Gal premiered on SundanceTV and was cited by the Village Voice in its annual survey of the year's best undistributed films.

She did guest shots on Hey Arnold!, Ally McBeal and Law & Order: Special Victims Unit, and had key roles in the independent features Swing (2003), Latter Days (2003) and Fascination (2004).

Hopper's untimely death in spring 2010 occurred before Yellen could begin postproduction, and she eventually launched a crowd-funding campaign to complete the film.

Following a recurring role on Rizzoli & Isles from 2011 to 2012, Bisset returned to the UK to film Stephen Poliakoff's 1930s jazz drama series Dancing on the Edge, which started on BBC2 in 2013.

[30] On the indie circuit, Bisset kept busy with roles in four features in 2018: Head Full of Honey, which reunited her with The Deep co-star Nick Nolte; Backstabbing for Beginners (opposite Ben Kingsley); Here and Now with Sarah Jessica Parker; and Asher with Famke Janssen and Ron Perlman.

[32] She is set to star with Dominic Monaghan in Long Shadows (2024), which marks her first western since The Life and Times of Judge Roy Bean.

[34] In 1989, the year she headlined Paul Bartel's risqué comedy Scenes from the Class Struggle in Beverly Hills, the New York Daily News published an article about her titled "Bad Girl Bisset".

Forbes pointed out that, despite her status as a heterosexual sex symbol, Bisset incidentally has acquired a loyal gay fanbase, which the actress herself was unaware of for many years.