Ghostley was best known for her roles as bumbling witch Esmeralda (1969–72) on Bewitched, as Cousin Alice (1970–71) on Mayberry R.F.D., and as Bernice Clifton (1986–93) on Designing Women, for which she received an Emmy nomination for Best Supporting Actress in a Comedy Series in 1992.

In the recurring sketch "Arthur and Agnes", Gleason played a loudmouthed, inconsiderate braggart talking to Ghostley on her front stoop.

Gleason's character treated her thoughtlessly for several minutes before walking away, leaving Ghostley alone to confide to the audience, "I'm the luckiest girl in the world!"

Towards the end of the 1965–66 season, actress-comedian Alice Pearce, who was featured as nosy neighbor Gladys Kravitz on Bewitched, died.

In September 1969, after the death of actress Marion Lorne, who played Aunt Clara, Ghostley joined Bewitched as a semiregular in the role of Esmeralda, a shy witch who served as a maid and babysitter to the Stephens' household.

[7] During her two years on Bewitched, Ghostley also joined the cast of Mayberry R.F.D., playing Cousin Alice after Frances Bavier's character, Aunt Bee, was written out of the series.

[6] Between 1986 and 1993, Ghostley portrayed Bernice Clifton, the slightly off-kilter, eccentric friend of Julia and Suzanne Sugarbaker's mother, Perky, on Designing Women.

Among many other guest roles, she appeared in a flashback episode as the crazed mother-in-law of Dorothy Zbornak (Bea Arthur) on The Golden Girls.

[6] Among her roles in motion pictures, Ghostley appeared in To Kill a Mockingbird (1962),[2] playing Stephanie Crawford, the neighborhood gossip.

[citation needed] Ghostley received a Tony nomination in 1963 for different roles she played in the Broadway comedy The Beauty Part.