Segueing to acting in the mid-80s, Russo landed the role of Eden, literary agent and romantic interest of the title character, on the short-lived adventure series "Sable" (ABC, 1987-88). It marked the first of many seemingly thankless wife of "girlfriend" roles that she went on to play, like her feature debut in David S Ward's baseball comedy "Major League" (1989) as a librarian reluctant to rekindle a romance with Tom Berenger. She played spouse to James Belushi in "Mr. Destiny" (1990) and Michael Keaton in "One Good Cop" (1991) before landing the career-making role of Detective Lorna Cole in Richard Donner's "Lethal Weapon 3" (1992). As the no-nonsense Internal Affairs officer who blossoms when she interacts with Riggs (Mel Gibson) and Murtaugh (Danny Glover), Russo displayed not only her acting ability but her facility as an action heroine. Her romantic scenes with Gibson were both humorous (they compare battle scars) and sensual. Their onscreen chemistry led to a reunion as the concerned parents of a kidnapped child in "Ransom" (1996) and the unnecessary but inevitable "Lethal Weapon 4" (1998).
While she was clearly capable of more, Russo seemed content to rest in the niche of playing strong women who took a back seat to men like her competent Secret Service agent (and romantic interest for Clint Eastwood) in Wolfgang Petersen's "In the Line of Fire" (1993) and her ex-wife and fellow scientist opposite Dustin Hoffman in the thriller "Outbreak" (1995). Barry Sonnenfeld gave her a slight change-of-pace, casting her as a B-movie actress with a penchant for blonde wigs and tight skirts in "Get Shorty" (also 1995). That Russo managed to hold her own against such powerful screen presences as John Travolta, Danny DeVito and Gene Hackman, as well as displayed impeccable comic timing brought her critical praise. Continuing on a similar theme, she lent her sexy presence to the role of a small-town shrink caught between a golf pro (Don Johnson) and his buddy (Kevin Costner) in Ron Shelton's breezy but lightweight "Tin Cup" (1996).
Russo finally headlined a film, the biopic "Buddy" (1997), in which she essayed the real-life eccentric millionaire Gertrude Lintz who raised a menagerie on her estate. While she delivered a fine performance, the old adage about working with children and animals proved truthful: most of the actors were upstaged by the chimpanzees dressed like humans and the titular gorilla, Gertrude's favorite of her "collection.” Critics panned the film and audiences stayed away—her attempt to carry a film and prove her bankability failed.
Still sexy and vital in her mid-40s, Russo confounded Hollywood stereotypes by delivering her most accomplished performance as an insurance investigator who romances the prime suspect in an art theft in the remake of "The Thomas Crown Affair" (1999). At first concerned over the required nudity and the frank sexuality of the character, the devoutly Christian actress reportedly prayed before accepting the role ("I don't know where in the Bible it says 'Don't be nude in motion pictures.'"). At the director's insistence, Russo also adopted a more sophisticated look, cropping her hair and dyeing it red as well as wearing a sleek wardrobe. Her onscreen chemistry with co-star Pierce Brosnan (abetted by several steamy love scenes) helped to impress reviewers and audiences, winning her new fans. Russo followed with another sultry female, Natasha Fatale, in the mixed live action-animated feature "The Adventures of Rocky and Bullwinkle" (2000).
After the embarrassment of “Rocky and Bullwinkle,” Russo took another misstep with the limp action comedy “Showtime” (2002), playing the producer of a reality show that pairs a showboating actor (Eddie Murphy) and an old-school cop (Robert De Niro). She then played an unhappy housewife with an unhappy daughter (Zooey Deschanel) in “Big Trouble” (2002), a ensemble comedy about a group of people brought together by a suitcase nuke at a Miami airport. The feature languished for six months because of the terrorist attacks on September 11, 2001 and was finally released with little fanfare or audience attendance—something about bombs and hijacked airplanes kept people away. Russo spent a few years away from film, but returned in 2005 to star alongside Al Pacino and Matthew McConaughey in “Two For the Money,” a gambling drama about a college basketball player (McConaughey) turned to sports wagering after being groomed by a consultant (Pacino) who notices his knack for predicting the right outcome for games.
She then starred opposite Dennis Quaid in the romantic comedy, “Yours, Mine and Ours” (2005), a remake of the 1968 Lucille Ball-Henry Fonda comedy about two high school sweethearts who reunite after the deaths of their spouses and rush to get married only to discover their children hate the new arrangement.