In 1957, she and Julie Newmar appeared on Broadway in the hit musical Li'l Abner. Her album It's Time for Tina was also released that year, with songs such as "Embraceable You" and "I'm in the Mood for Love."
She made her Hollywood film debut in 1958 in God's Little Acre. She became an in-demand leading lady for major stars like Robert Taylor, Richard Widmark and Robert Ryan, often playing somber roles quite unlike the glamorous pinup photographs and Playboy pictorials she had become famous for in the late 1950s. Further roles followed, on Broadway and in Italian cinema and Hollywood, but they failed to boost her to stardom. Among her more notable Italian film credits was the historical epic Viva L'Italia! (1960), directed by Roberto Rossellini, that concerned Garibaldi's efforts to unify the Italian states in 1860.
When Louise returned to the United States, she began studying with Lee Strasberg and eventually became a member of the Actors Studio. She appeared in an early 1960s "beach movie" For Those Who Think Young, with Bob Denver, prior to the development of Gilligan's Island.
In 1964, she left the Broadway musical Fade Out - Fade In to portray movie star Ginger Grant on the TV sitcom Gilligan's Island, after the part was turned down by Jayne Mansfield. However, she was unhappy with the role and worried that it would typecast her. The role did make Louise a pop icon of the era, and in 2005 an episode of TV Land Top Ten ranked her as second only to Heather Locklear as the greatest of television's all-time sex symbols.
After the series ended in 1967, Louise continued to work in film and made numerous guest appearances in various television series. She appeared as a doomed suburban housewife in the original The Stepford Wives (1975), and both the film and her performance were well received. She attempted to shed her comedic image by essaying grittier roles, including a guest appearance as a pathetic heroin addict in a 1974 Kojak episode, as well as a co-starring role as an evil Southern prison guard in the 1976 ABC TV Movie Nightmare in Badham County. Her other TV movies of the period included Look What's Happened to Rosemary's Baby (1976), SST: Death Flight (1977), and Friendships Secrets and Lies (1979).
The question "Ginger or Mary Ann?" is regarded to be a classic pop-psychological question when given to American men of a certain age as an insight into their characters, or at least their desires as regarding certain female stereotypes.
Despite her own successes, she has declined to participate in any of the four reunion television movies for Gilligan's Island, but did appear on a few talk shows and specials for some Gilligan's Island reunions, including Good Morning America (1982), The Late Show (1988) and the 2004 TV Land award show, with the other surviving cast members. In the 1990s, she was reunited with costars Bob Denver, Dawn Wells, and Russell Johnson in cameo appearances on an episode of Roseanne. She didn't reunite with them however for the TV-movie Surviving Gilligan's Island: The Incredible True Story of the Longest Three Hour Tour in History (2001), co-produced by Dawn Wells, because she objected to the way she was portrayed in the film. Her relations with series star Denver were rumored to be strained, but in 2005, she wrote a brief, affectionate memorial to him in the year-end "farewell" issue of Entertainment Weekly.
Louise appeared as a semi-regular character in the prime-time soap opera Dallas and made an appearance on Married... with Children. In 1985, Louise played the second and final Taylor Chapin on the syndicated soap opera Rituals. Later film roles included a co-starring appearance in the Robert Altman comedy O.C. and Stiggs (1987), as well as the independently made satire Johnny Suede (1992) starring Brad Pitt.
From 1966 to 1974, Louise was married to radio and TV announcer/interviewer Les Crane, with whom she has one daughter, Caprice Crane (born 1974), who became an MTV producer and a novelist. Crane's first novel, Stupid and Contagious, was published in 2006, and was warmly dedicated to her mother. Louise now resides in New York City. Since 1995, she has worked as a volunteer teacher with Learning Leaders, a non-profit organization dedicated to providing tutoring to New York City school children. She has written two children's books: Sunday: A Memoir (1997) and When I Grow Up (2007).