Rue obtained her love of entertaining from her mother, who brought her to dance class when she was a young child. As one of the most popular students in high school, she was voted "most likely to succeed" by her peers. She was involved in theatrical productions at school and helped to run a dance academy. During her senior year of high school, Rue ran the dance academy by herself.

After graduating from Ardmore High School, Rue continued her studies at the University of Tulsa where she graduated cum laude with a double major in German and theatre arts and a minor in French. Soon after graduating she decided to move to New York City to look for work as a professional actress. Rue studied acting under theatre legend Uta Hagen. Her first job, however, ended up being in Erie, Pennsylvania at the Erie Playhouse. It was during this time that Rue met the man who would be her first husband, Tom Bish. They were married in 1958, less than a year after meeting. The marriage faded quickly and to make matters worse, Rue discovered that she was pregnant. Her son, Mark, was born in Ardmore, Oklahoma, and soon thereafter, in 1959, Rue and Tom filed for divorce.

After the birth of her son, Rue lived with her parents in Ardmore for a while and opened a dance and acting school. In 1959, soon after her divorce from Tom Bish, she married a good friend, Norman Hartwig. Rue and Norman realized that they were not actually in love but rather were just very good friends and divorced in 1961. After the divorce, she moved back to New York City. In the early 1960s, Rue began her film career with such B-list flicks as The Grass Eater and Door-to-Door Maniac, and exploitation films--Hollywood After Dark (produced in 1964) and Five Minutes to Love (1963).

During the 1960s, she also began a professional career in theater, performing on and off Broadway, in such shows as MacBird!, Sticks and Bones, and Plaza Suite. In 1964, Rue landed a role in the theatrical production The Secret Life of Walter Mitty, where she became acquainted Peter DeMaio, a fellow actor. Soon after meeting, they were wed. The tumultuous union came to an end after seven years, in 1971. In 1970 Rue landed her first major television role on the soap opera Another World as the character Caroline Johnson.

It was in the early 1970s that Hollywood finally began to discover Rue. She starred in a production of Jimmy Shine with Dustin Hoffman and was given a role on a soap opera Another World. However, it was her performance in Tonight In Living Color that lead producer Norman Lear to offer her a guest appearance on an episode of his sitcom All In The Family in 1972. Lear was so impressed by Rue's tremendous talent and ability to do comedy that in 1973 he decided to cast her in his series Maude (1972-1978) starring Bea Arthur.

In 1976, brought together by a mutual friend, Rue met the man who would become her fourth husband, Gus Fisher. In 1976, Gus and Rue were married in a traditional Greek wedding. Gus decided to pursue work in commercial real estate and ended up spending more time with his clients than his wife. In 1979, the marriage came to an end.

After Maude was canceled, Norman Lear offered Rue a television series of her own, Apple Pie, in which she played the lead role and co-starred with Dabney Coleman and Jack Gilford. Unfortunately, the show only lasted two episodes before it was canceled when ABC changed executives (however, seven episodes were actually made). Maude's success made Rue into a popular television actress and in 1982, she was offered a role in the comedy series Mama's Family (which first aired in January 1983). However, Rue was unhappy with the way her character was being written and only appeared on the show until 1985, when her character was killed off.

While in her dressing room on the set of Mama's Family, Rue experienced a sharp pain under her right rib and was taken to the emergency room for a severe gall bladder attack. When she woke up from the operation, she was unable to breathe. She had developed Adult Respiratory Distress Syndrome, a disease of the lungs that can onset after surgery and is almost always fatal. She spent three weeks in the hospital, including five days in the ICU with a questionable chance to survive, before returning home to recover.

After two more weeks, Rue returned to Mama's Family. However, she could only speak very softly, as she had lost her voice due to her vocal chords becoming damaged while she was receiving treatment in the hospital. It was years before she finally regained a full vocal range. In 1984, Rue became reacquainted with and married her high school sweetheart Tom Keel, but they divorced after only a year. In 1985, Rue was offered what is undoubtedly her best-known television role on the hit comedy series The Golden Girls, where she portrayed the character of the over-sexed, highly confident Southern belle with a hearty appetite for men, Blanche Devereaux.

In 1987, Rue was recognized for her outstanding work on The Golden Girls with an Emmy award for best lead actress in a comedy series. In 1990, she launched her own television production company, Nugget Entertainment. The company's first project was a made-for-TV movie, To My Daughter, in which Rue starred. However, a year after its commencement, Nugget joined forces with Imagine Entertainment (Rue is no longer involved in the project).

In 1992, The Golden Girls ended its seven-year run when Bea Arthur decided to leave the show. The next season, the remaining actresses were cast in a follow-up series, The Golden Palace, which only lasted one season. During the years of The Golden Girls and The Golden Palace, Rue became one of the top television actresses of the 1980s and was in several movies and guest starred on numerous television shows.

Since the end of The Golden Palace, Rue has performed in several theatrical productions both on, and off Broadway (one of which being Bye, Bye Birdie with The Civic Light Opera). She has promoted her own line of clothing for women over forty, appropriately called Very Rue (the name was later changed to A Touch of Rue). She has also become heavily involved in animal rights and is the honorary chairperson for the organization, PETA, People for the Ethical Treatment of Animals.

In late May of 1997, while she was performing in a play in New York City, Rue met Morrow Wilson, a friend of the play's producer (and also an actor/producer himself). Morrow assisted Rue in learning her lines but their relationship suddenly became intimate when Rue discovered a lump under her right arm. On June 6, 1997, Rue was diagnosed with breast cancer. This was also the day that Morrow first told Rue that he loved her.

On June 10, Morrow proposed and the couple was wed on Christmas day of 1997. The wedding was held at the Waldorf Astoria, one of New York City's most luxurious hotels, with 180 guests in attendance. Rue has also written several short stories, a screenplay, and musicals. She wrote and produced her own stage musical, Oedipus Schmedipus, As Long As You Love Your Mother, which was staged in Los Angeles in 1991. In 1999, she had a role on the WB network's short-lived drama series Safe Harbor as Grandma Loring.

Rue is now completely cancer-free, and she and Morrow are still happily married and living in Manhattan with their cat, Bianca. She continues to do work in animal rights activism, breast cancer awareness, theater and television/film. In the fall and winter of 2001-2002, Rue starred on Broadway in the star-studded hit revival of The Women along with Kristen Johnston, Jennifer Tilly, Cynthia Nixon and Jennifer Coolidge. In the spring of 2003, she starred opposite Mark Hamill in Six Dance Lessons In Six Weeks. Rue also has a role in the feature film The Fighting Temptations, with Cuba Gooding Jr. and Beyonce Knowles.