The actress' manager, Barbara Lawrence, has confirmed the star died at a hospital in New York, surrounded by her family. She was 76.
Lawrence tells People.com, "She passed away at 1am this morning. She had a massive stroke... She went in peace."
Born Eddi-Rue McClanahan, the star enjoyed a career spanning more than five decades. She began acting on the New York stage in the 1950s and made her Broadway debut in 1969 in musical Jimmy Shine, opposite a young Dustin Hoffman.
Her screen breakthrough came in 1970 when she landed a role on U.S. soap Another World and she went on to star in another popular TV show, Where the Heart Is, before she was cast in hit 1970s sitcom Maude.
But McClanahan's most famous role was as man-crazed Blanche Devereaux in The Golden Girls, in which she starred alongside Betty White, Bea Arthur and Estelle Getty.
The show first aired in 1985 and ran for seven years, earning her an Emmy Award in 1987 for Outstanding Lead Actress in a Comedy Series.
She successfully battled breast cancer in 1997 but her later years were marred by ill health and she underwent triple bypass surgery in 2009, before suffering a minor stroke in January (10).
She was married six times and is survived by her son, Mark Bish, from her first marriage to Tom Bish. She separated from her sixth husband, Morrow Wilson, earlier this year (10).
White, who is the last surviving star of The Golden Girls, has paid tribute to her late pal.
A statement from the 84-year-old actress reads, "Rue was a close and dear friend. I treasure our relationship. It hurts more than I ever thought it would, if that's even possible."
It has been a rough three years for fans of the beloved show - Getty died in 2008 and Arthur lost a battle with cancer last year (09).