In 1972, Russo was spotted at a Rolling Stones concert by a scout and manager John Crosby from International Creative Management. She was signed to the Ford Modeling Agency and began modeling shortly after, appearing on the cover of several magazines, including Vogue. Russo spent the majority of the 1970s and early 1980s as a successful model, but later began to study acting.

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 martial arts-practicing internal affairs detective Lorna Cole in Lethal Weapon 3 (and again in Lethal Weapon 4). Throughout the 1990s, Russo appeared in a number of high-profile thrillers that were hugely successful at the box office, including In the Line of Fire, Outbreak, Ransom and The Thomas Crown Affair. She tried her hand at comedy in