Barbeau was born and raised in Sacramento, California, in 1945, the daughter of Armene (née Nalbandian) and Joseph Barbeau, who was a public relations executive for Mobil Oil. Her mother was of Armenian descent and her father's ancestry included French-Canadian, Irish, and German. She has a sister, Jocelyn, and a half brother on her father's side, Robert Barbeau, who still resides in the Sacramento area. She attended Del Mar High School in San Jose, California. In her autobiography, Barbeau says that she first caught the show Business bug while entertaining troops at army bases throughout Southeast Asia, touring with the San Jose Civic Light Opera.

In the late 1960s, Barbeau moved to New York City and worked "for the mob" as a go-go Dancer. She made her Broadway debut in the chorus of Fiddler on the Roof, and later took the role of Hodel, Tevye's daughter; Bette Midler played her character's sister. She left Fiddler in 1971 to play the leading role of Cookie Kovac in the off-Broadway nudie musical Stag Movie. Barbeau, as Cookie Kovac, and Brad Sullivan, as Rip Cord, were "quite jolly and deserve to be congratulated on the lack of embarrassment they show when, on occasion, they have to wander around stark naked. They may not be sexy but they certainly keep cheerful," wrote The New York Times theater critic Clive Barnes in an otherwise negative review. Barbeau went on to star in more than 25 musicals and plays, including Women Behind Bars, The Best Little Whorehouse in Texas, and Grease. She received a Theater World Award and a 1972 Tony Award nomination for her portrayal of tough-girl Rizzo in Grease.

Barbeau played a cameo role in Rob Zombie's Halloween, a "reimagining" of the 1978 film of the same name, written and directed by her first husband, John Carpenter. Her scene was cut from the theatrical version of the film but is included in the DVD version.

Barbeau was married to Director John Carpenter from January 1, 1979, to 1984. The two met on the set of his television movie, Someone's Watching Me! (1978). The couple had a son, John Cody (born May 7, 1984) shortly before they separated. During their marriage, the couple lived in Hollywood Hills but according to Barbeau remained "totally outside Hollywood's social circles".

Barbeau's then-husband, Director John Carpenter, cast her in his horror film, The Fog (1980), which was her first theatrical film appearance. The film was released on February 1, 1980, and was a theatrical success, grossing over $21 million in the United States alone, and establishing Barbeau as a genre film star. She subsequently appeared in a number of early-1980s horror and science fiction films, a number of which have now become cult film classics, including Escape from New York (also from Carpenter), Creepshow and Swamp Thing. Of her screen work with Carpenter, Barbeau has stated: "John is a great Director. He knows what he wants and he knows how to get it. It's simple and it's easy [working with him]."

She also appeared in the high-grossing Burt Reynolds comedy The Cannonball Run (1981)—her character wins the race—and as the shrewish wife of Rodney Dangerfield's character in Back to School (1986). Barbeau also starred, alongside Future talk show host Bill Maher and Actress and model Shannon Tweed, in the comedy Cannibal Women in the Avocado Jungle of Death (1989).

In the 1990s, Barbeau mostly appeared in made-for-television films such as Scott Turow's The Burden of Proof (1992), as well as playing Oswald's mother on The Drew Carey Show and gaining new fame among animation fans as Catwoman on Batman: The Animated Series and Gotham Girls.

Barbeau married actor/playwright/producer Billy Van Zandt, thirteen years her junior, on December 31, 1992. The two met in 1991 when Barbeau was cast in the west coast premiere of his play, Drop Dead! Billy is the half-brother of musician/actor Steven Van Zandt. She gave birth to twin boys, Walker Steven and william Dalton Van Zandt, on March 17, 1997, at age 51, claiming she was the only one on the maternity ward who was also a member of AARP.

In 1998, Barbeau released her debut album as a folk singer, the self-titled Adrienne Barbeau. She starred in the cartoon series Totally Spies! doing the voice of villainess Helga Von Guggen in seasons 1, 2 and 4.

She also worked as a television talk show host and a weekly book reviewer for KABC talk radio in Los Angeles. In 1999, she guest starred in the Star Trek: Deep Space Nine episode "Inter Arma Enim Silent Leges" as Romulan Senator Kimara Cretak. In 1994, she also appeared in the Babylon 5 episode "Spider in the Web" as Amanda Carter.

From 2003 to 2005, she starred on the HBO series Carnivàle. From March to May 2006, she starred as Judy Garland in the off-Broadway play The Property Known as Garland.

Barbeau's autobiography There Are Worse Things I Could Do was published in 2006 by Carroll & Graf, rising to #11 on the Los Angeles Times best-sellers list. In July 2008, her first novel, Vampyres of Hollywood, was published by St Martin's Press. The novel was co-written by Michael Scott. The first sequel Love Bites was published in 2010, and the second, Make Me Dead was published in 2015.

Also in 2009, Barbeau had guest spots in the first episode of Showtime's hit series Dexter (Season 4), as well as on Grey's Anatomy.

She voiced the Greek goddess Hera in the video game God of War III released for the PlayStation 3 in March 2010. In August 2010, she began a role on the long-running ABC daytime drama General Hospital. In 2012, she voiced UNSC scientist Dr. Tilson in the highly anticipated game Halo 4, released on the Xbox 360 in November 2012. She voiced characters in the Mad Max video game of the same name.

On October 22, 2013, she made a guest appearance on the FX series Sons of Anarchy.

In 2015, she assumed the role of Berthe in Pippin with the Broadway Touring Company of the renowned musical. In the same year she also began to provide the Descriptive Video Service track for visually-impaired individuals for some episodes of the Fox series Empire.

Barbeau appeared on Ken Reid's TV Guidance Counselor podcast on February 19, 2016.