Sirtis was born in East End of London, the daughter of working class Greek parents Despina, a tailor's assistant, and John Sirtis. She was raised in North London and emigrated to the U.S. in 1986, later becoming a naturalized U.S. citizen. She is married to rock guitarist Michael Lamper (21 June 1992 - present). Her younger brother, Steve, plays football in Greece and played for Columbia University in the early 1980s. She auditioned for drama school against her parents' wishes, ultimately being accepted to the Guildhall School of Music & Drama.

Sirtis started her career as a member of the repertory company at the Connaught Theatre, Worthing, West Sussex in 1976. Directed by Nic Young, she appeared in Joe Orton's What the Butler Saw and as Ophelia in Hamlet.

Before her role in Star Trek, Sirtis was featured in provocative, sexually-themed supporting roles in several movies. In the Faye Dunaway film The Wicked Lady, she engaged in a topless whip fight with Dunaway. In the Charles Bronson sequel Death Wish 3, Sirtis's character is a rape victim. In the film Blind Date, she appears in a topless scene as a prostitute who is murdered by a madman.

She has an established record of British television work, appearing in Minder, Raffles, and The Return of Sherlock Holmes among other things. She played the stewardess in the famous Cinzano Bianco television commercial starring Leonard Rossiter and Joan Collins, in which Collins was splattered with drink.

Gene Roddenberry was inspired to ask the exotic-looking Sirtis 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 and Denise Crosby initially tried out for each other's eventual role on The Next Generation. Sirtis's character was going to be named Lt. Macha Hernandez, the Security Chief. Gene Roddenberry decided to switch them, and Macha Hernandez became Natasha Yar. Sirtis recalls that on the day she received a call offering her the role of Deanna Troi, she was actually packing to return to England, because her six-month visa had ended.

Deanna Troi was a half-human, half-Betazoid. Her Betazoid abilities allowed her to read the emotions of others. Her position on the Enterprise-D was ship's counsellor, looking after the crew's well-being and a trusted advisor to Captain Picard with a position seated next to him on the Bridge.

Initially, the writers found it difficult to write for Troi and even left her out of four of the first season episodes. Sirtis felt her job was in jeopardy after the first season but was overjoyed when Gene Roddenberry took her aside at Jonathan Frakes' wedding and told her that the season two premiere episode, "The Child", would center on Troi.

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

She has stated her favourite episode is season six's "Face of the Enemy", in which Troi is kidnapped and surgically altered to pose as a Romulan. Troi's switching to a standard Starfleet uniform that 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. So I got all my brains back and I was allowed to do things that I hadn't been allowed to do for five or six years. I went on away teams, I was in charge of staff, I had my pips back, I had phasers, I had all the equipment again, and it was fabulous. I was absolutely thrilled."

During her time on the show, she became close friends with her co-stars Jonathan Frakes (who played her on-again/off-again lover Commander Riker), Michael Dorn (Lieutenant Worf, also an on-screen love interest) and Brent Spiner. Cast members Spiner and Dorn were groomsmen at her wedding.