[1] Sirtis started her career as a member of the repertory company at the Connaught Theatre, Worthing, West Sussex, in 1976.

Sirtis appeared in Raffles (1977), Who Pays the Ferryman (1977), Hazell (1978), Minder (1979), Up the Elephant and Round the Castle (1985), and The Return of Sherlock Holmes (1986).

When casting Star Trek: The Next Generation, Gene Roddenberry was inspired to ask Sirtis, whose appearance he considered "exotic", to audition for a role after seeing the film Aliens with Bob Justman, which featured the prominent Latina character Vasquez, played by Jenette Goldstein.

Sirtis recalls that on the day she received the call offering her the role, she was actually packing to return to Britain because her six-month visa had expired.

Sirtis felt her job was in jeopardy after the first season, but was overjoyed when Roddenberry took her aside at Jonathan Frakes' wedding and told her that the season-two premiere episode would center on Troi.

[11] Sirtis appeared in all seven seasons of Star Trek: The Next Generation, and her character was developed from a more passive therapist to a tougher Starfleet officer.

She has stated her favourite episode is season six's "Face of the Enemy", in which she is kidnapped and surgically altered to pose as a Romulan.

Troi's switching to a standard Starfleet uniform in the same season in "Chain of Command" elevated the character's dignity in Sirtis' eyes, and her enthusiasm in playing her, with Sirtis commenting, "It covered up my cleavage and, consequently, I got all my brains back, because when you have a cleavage you can't have brains in Hollywood.

[13] She wore black-coloured contact lenses during the seven-year run of Star Trek: The Next Generation and the subsequent films because her character had black eyes.

Sirtis was delighted to get the chance to do some comedy in Star Trek: First Contact and said, "I loved it because it opened the door to a different side of Troi we'd never seen before.

"[16] Sirtis stated of her role in Star Trek: Nemesis, "I sort of had an inkling that I was going to have a good part in this film because John Logan was such a big fan of the character.

In 1992, she appeared in an episode of the short-lived series The Fifth Corner and had a cameo in the horror/fantasy film Waxwork II: Lost in Time.

In 2001, Sirtis made a highly publicised appearance on the long-running British hospital drama Casualty.

[21] Sirtis had a minor role in the Academy Award-winning ensemble film Crash as the wife of the Persian shopkeeper.

She provided the voice for Matriarch Benezia in the critically acclaimed video game Mass Effect on Xbox 360, PlayStation 3 and PC.

Sirtis said of her role, "I actually play the Deputy Attorney General of the United States, so I'm a bad guy, a mean lawyer, which was fantastic.

She co-starred in the British film 31 North 62 East as the prime minister's top aide; it had a limited theatrical release in the UK.

In May 2010, Sirtis announced that she would be providing the voice for comic-book villainess Queen Bee in the Young Justice animated series.

[26] Her character, Orli Elbaz, succeeds Eli David (portrayed by Michael Nouri) and was introduced in the season-10 episode "Berlin", which aired in April 2013.

[27] In 2019, Sirtis made her London West End stage debut in Dark Sublime, playing the character of Marianne, a freelance actor and now-forgotten icon of a British sci-fi TV show, whose encounter with a fan changes both of their lives.

[31][32] In 2021, Sirtis moved back to London, citing Lamper's death, growing tensions in the U.S. surrounding the COVID-19 pandemic response, and a desire for career opportunities in British film and television.