Donna Mills left the University of Illinois before turning twenty to pursue a career as a dancer and an actor, appearing in theatrical productions in Chicago, including several at the Drury Lane Theatre. She was cast in a touring production of "My Fair Lady" which brought her to New York. In 1964, Mills made her TV debut in a short-term role on the daytime soap "The Secret Storm" and was a regular on the short-lived variety series "The Steve Lawrence Show" (CBS, 1965). The following year, she was in the original cast of Woody Allen's Broadway hit "Don't Drink the Water". In 1967, Mills made her feature film debut with a small role in Larry Peerce's "The Incident". Still based in New York, she spent three years as former nun Laura Donnelly Elliot on the CBS daytime drama "Love Is a Many Splendored Thing" (1967-70).

Now established as a working actor and having won attention with her soap role, Mills relocated to the West Coast to try to make the breakthrough to primetime. An appearance in the Burt Reynolds' vehicle "Dan August" led to her being cast as Clint Eastwood's girlfriend in "Play Misty For Me" (1971), which also marked Eastwood's directorial debut. While the film was a moderate success, Mills found additional features elusive. Instead, she concentrated on the small screen, often playing a woman in distress. An exception was her turn as Larry Hagman's wife in the sitcom "The Good Life" (NBC, 1971-72), in which they were servants for a wealthy couple. Mills also carved a niche for herself in TV-movies. She offered strong performance as an undercover policewoman in "The Bait" (ABC, 1973) and a wife fleeing from her husband, a spy, in "Woman on the Run" (CBS, 1977).

But it was her portrayal of venal yet sexy Abby on "Knots Landing" that moved her to the front of the ranks of small screen stars. As part of her storyline, she was reunited with Hagman, who brought his J.R. Ewing from "Dallas" to the spin-off. After a nine-year run on the primetime soap, during which Abby became a wealthy woman, bedded and wedded Gary Ewing (Ted Shackleford), had an affair with a mob-connected politician, was taken hostage, and eventually left her husband for his opponent in a political campaign, Mills left to pursue other ventures. She went on to star in numerous TV-movies and specials (including a number of Bob Hope's NBC vehicles). Among her more notable efforts, were as a mother who caring for a child in "He's Not Your Son" (CBS, 1984) and as a busy executive who falls for her male secretary in the comedy "The Oldest Living Bridesmaid" (CBS, 1991). Mills began developing much of her own material in the 90s, serving as executive producer on efforts like "In My Daughter's Name" (CBS, 1992) and "My Name Is Kate" (ABC, 1994). She was a con artist in "An Element of Truth" (CBS, 1995) and a woman who allows her husband to be turned into the perfect spouse in "The Stepford Husbands" (CBS, 1996). Mills rejoined the world of primetime soap opera in 1996 when she landed the recurring role of the birth mother of troubled fashion designer Jane Mancini (Josie Bissett) on Fox's "Melrose Place".