Russo started a modeling career after allegedly being spotted at a 1972 Rolling Stones concert by John Crosby, an agent from International Creative Management. With his encouragement, Russo applied to, and was signed by, Ford Modeling Agency, and went on to appear on magazine covers for Vogue, Mademoiselle, and Cosmopolitan, as well as advertisements for perfume and cosmetics.
By her 30th birthday, demand for her as a model began to dwindle. She did a few more commercials and then turned her back on modeling and show business for a while. She began to study theater and acting, and began appearing in theater roles at small regional theaters in Los Angeles and elsewhere in California. At one point, she took acting lessons from veteran actor Allan Rich. They were interviewed on CNN in 1980.
Russo made her television series debut in 1987, with a supporting role in the TV series Sable. Two years later, she made her debut in film as the girlfriend of the Tom Berenger character in Major League. Her breakthrough role is generally considered to be her part as internal affairs detective Lorna Cole in Lethal Weapon 3 (and again in Lethal Weapon 4) opposite Mel Gibson.
Throughout the 1990s, Russo appeared in a number of thrillers including In the Line of Fire with Clint Eastwood, Outbreak with Dustin Hoffman, Ransom (directed by high school classmate Howard where she worked again with her Lethal Weapon co-star Gibson) and the remake of The Thomas Crown Affair with Pierce Brosnan. She attained a certain degree of cult status from her performance in Freejack, alongside of Emilio Estevez, Mick Jagger, and Anthony Hopkins.
She also tried her hand at comedy in Tin Cup with Kevin Costner, Get Shorty with John Travolta and as Natasha Fatale in the live-action film version of The Adventures of Rocky and Bullwinkle. She starred in at least one major studio film per year from 1992 to 2002.
In 2005 Russo co-starred with Al Pacino in Two for the Money and with Dennis Quaid in Yours, Mine and Ours. In 2011, six years after resting from acting, she appeared in the superhero film, Thor, as Frigga, the mother of the titular hero.