Mills began her acting career on television with a guest role on the CBS daytime soap opera The Secret Storm in 1966. Following this she gained a regular role as ex-nun Laura Donnelly on the soap Love is a Many Splendored Thing, which she played from 1967 to 1970. Mills appeared on Broadway in Woody Allen's comedy, Don't Drink the Water, as the Sultan of Bashir's wife.

In 1971, Mills co-starred with Clint Eastwood in the thriller Play Misty For Me, which has remained her most prominent movie role to date. Prior to signing up a contract for Universal Studios in 1972 (much like her future Knots Landing co-stars Joan Van Ark and Kevin Dobson did at the same time), Mills spent much of the 1970s appearing as a guest television shows such as The Six Million Dollar Man, Hawaii Five-O, The Love Boat, CHiPs, The Oregon Trail, Quincy, M.E., Thriller, Police Woman, and Fantasy Island, as well as several made-for-TV movies.

In 1980, she landed her most prominent role — that of scheming, manipulative Abby Cunningham on the long-running primetime soap opera Knots Landing, a role she played until 1989. After leaving the series, Mills concentrated on TV movies, several of which she co-produced. She returned to Knots Landing for its final episode in 1993, and again for the reunion mini-series Knots Landing: Back To The Cul-De-Sac in 1997. In between, she had a brief recurring guest role as Josie Bissett's mother on the popular 1990s soap opera Melrose Place. In more recent years, Mills has continued to make TV movies as well as guest appearances in series such as Cold Case (season 4, episode 13 "Blackout") and Nip/Tuck (in which she guest-starred with fellow Knots Landing star Joan Van Ark).

In 2005, she reunited with the Knots Landing cast for the reunion, Knots Landing: Together Again, in which the stars reminisced about the show.

Outside of acting, in 1986 Mills released "The Eyes Have It", an instructional video for achieving several different make-up looks. She went on to release her own line of cosmetics of the same name.

Mills appeared in a cover-featured (non-nude) pictorial for the November 1989 edition of Playboy Magazine.

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