The 76-year-old had undergone treatment for breast cancer in 1997. She later lectured to cancer support groups on "aging gracefully." In 2009, she had heart bypass surgery.
McClanahan had an active career in off-Broadway and regional stages in the 60s, but her most loved role came in 1985 when she co-starred with Beatrice Arthur, Estelle Getty and Betty White in "The Golden Girls."
In 1987, McClanahan snagged an Emmy for her work on the show.
In 1992 the show was cancelled. After that McClanahan, White and Getty reprised their roles in a short-lived spinoff called, "Golden Palace."
The last surviving "Golden Girl," Betty White said Thursday that she will truly miss her good friend.
"Rue was a close and dear friend. I treasured our relationship. It hurts more than I even thought it would, if that's possible," said White.
Through the years McClanahan continued working in television, on stage and in film.
One of the writers on "The Golden Girls" was "Desperate Housewives" creator Marc Cherry. He says his favorite character on the hit TV series was Blanche Devereaux.
"When I worked on 'The Golden Girls,' my favorite character to write for was Blanche Devereaux," said Cherry. "In the hands of lesser actresses, Blanche's vanity and sexual appetite would have been off-putting. But in Rue's brilliant hands, that character became one of the most beloved in the history of TV. Rue's kindness, generosity and enormous talent will be sorely missed."
In the early 1970s McClanahan co-starred with Arthur on the ground breaking and sometimes controversial sitcom, "Maude." After that, she was on to "Mama's Family."
Star Vicki Lawrence called McClanahan "an actor's actor." She says that when the actress was taken away from "Mama's Family" to do "Golden Girls," she cried.
She was married six times: Tom Bish, with whom she had a son, Mark Bish; actor Norman Hartweg; Peter D'Maio; Gus Fisher; and Tom Keel. She married husband Morrow Wilson on Christmas Day in 1997.
The Associated Press contributed to this story.