[6][7] Russo grew up with her mother and her sister, Toni (who was married to lyricist Bernie Taupin between 1979 and 1991),[8] and attended Burroughs High School, where her classmates included director Ron Howard.

[10] After allegedly being spotted at a 1972 Rolling Stones concert by John Crosby, an agent from International Creative Management,[11] Russo originally began her career as a model.

The poise she brought to her images made her the first choice for editorial shoots that demanded models with tenacity, whether she was bound for the boardroom in a power suit or posing on a beach with Tony Spinelli".

She made her feature film debut as the girlfriend of a former baseball star in Major League, a comedy written and directed by David S. Ward.

[15] In 1990, Russo appeared in the fantasy comedy film Mr. Destiny, with Jim Belushi, playing the wife in what was an alternate reality of an ordinary guy's life.

In 1991, she had her first leading film role in One Good Cop, as the wife of a New York City Police Department detective (played by Michael Keaton).

In 1992, Russo achieved breakout success with her role as internal affairs detective Lorna Cole, opposite Mel Gibson and Danny Glover, in the action film Lethal Weapon 3.

[22] In 1997, Russo portrayed exotic animal owner Gertrude Lintz in the little-seen comedy Buddy,[17][23] and in 1998, reprised her role in Lethal Weapon 4, the final film in the series, which made US$285.4 million.

[24] In 1999, she starred as an insurance investigator and the lover of a billionaire, alongside Pierce Brosnan, in the heist film The Thomas Crown Affair directed by John McTiernan.

Critic Kenneth Turan, in his review for the film, wrote: "[Her] smart, gritty performance is the best thing about this remake of the stylish caper movie Thomas Crown.

[29] The comedy Big Trouble, which was based on the novel by Dave Barry and featured her as a devoted mother, was originally scheduled for release on September 21, 2001, and had a strong advertising push.

[30] Russo starred in and produced the film Two for the Money (2005), with Al Pacino and Matthew McConaughey, playing the wife of a sports gambling agent.

[34] In 2010, Russo returned to the screen in the superhero film Thor, released in 2011, after being persuaded by director Kenneth Branagh in December 2009, who asked her to portray Frigga, the mother of the titular hero.

"[37] In 2014, Russo appeared as a morning news director, alongside Jake Gyllenhaal, in the crime thriller Nightcrawler, written and directed by her husband Dan Gilroy.

[42] In 2015, she reunited once again with Robert De Niro, playing an in-house massage therapist and his love interest, in the comedy The Intern, directed by Nancy Meyers.

[45] Russo starred with Morgan Freeman and Tommy Lee Jones in another comedy, Just Getting Started (2017), as the regional director of the luxury resort Villa Capri in Palm Springs, California.

[48] In Velvet Buzzsaw (2019), Russo worked again with Jake Gyllenhaal and Dan Gilroy, playing a tough art gallery owner haunted by the mysterious nature of a series of paintings by an unknown artist.