In the former series, broadcast from 1972 to 1978, McClanahan played Maude Findlay's best friend, Vivian Harmon. In the latter series, broadcast from 1985 until 1992, McClanahan portrayed the man-crazed Southern belle, Blanche Devereaux. She received an Emmy Award in 1987 for Outstanding Lead Actress in a Comedy Series for her work on The Golden Girls.

She began acting on stage in New York City in 1957, but her breakout role was of maniacal nanny Caroline Johnson on Another World from July 1970 - September 1971. In the show, while taking care of twins Michael and Marianne Randolph, Caroline fell in love with their father, John, and began poisoning their mother, Pat. Due in part to McClanahan's performance, the short-term role was extended to over a year before Caroline was finally brought to justice after kidnapping the twins. McClanahan expected negative fan reaction but was generally popular, even getting one letter advising her on the best poisons with which to kill Pat. Unlike a number of actors who become famous after leaving soaps, McClanahan has always praised daytime drama and the people who work in it.

A lifelong animal-rights advocate and vegetarian, McClanahan was one of the first celebrity supporters of People for the Ethical Treatment of Animals (PETA). She is also a lifelong supporter of the Democratic Party. In December 2003, she wrote a letter informing Democratic presidential nominee John Kerry that his pheasant hunting had cost him her vote.

She was diagnosed with breast cancer in June 1997 and survived with the help of cancer expert Dr. Larry Norton and her sixth husband, the much younger Morrow Wilson. She is also the mother of one child, a son, Mark Bish, from a previous marriage. Her autobiography, My First Five Husbands, is due in the spring of 2007.