Born Susan Jane Miller she was raised Catholic in Rockford, Illinois where she began modeling as a teenager. At the age of 20, she moved to California where she began her acting career. She landed a role in The Name of the Game (TV series), winning an Emmy Award for her role in 1969. From 1971 until 1976, she played Sally McMillan opposite Rock Hudson in the series McMillan and Wife and received four Emmy Award nominations.

She left the show to further her career as an actress in feature films and achieved a significant success in the vampire comedy Love At First Bite (1979).

After other film ventures failed to establish her, she returned to television, appearing in the comedy series Kate & Allie opposite Jane Curtin, from 1984 until 1989. She received a further three Emmy Award nominations for this role. Her niece Christa Miller (The Drew Carey Show, Scrubs) also had a role in that show.

Susan St. James was also a celebrity and commentator for World Wrestling Entertainment (WWE)'s Wrestlemania II event in 1986 along with Vince McMahon and Cathy Lee Crosby.

Saint James has acted very infrequently since then and has pursued other business ventures such as Seedling and Pip, a baby gift-basket business. She made a rare acting appearance in a guest spot as a defense attorney on the February 28, 2006, episode of Law & Order: Special Victims Unit

At age 21, she had married aspiring writer-director Richard Neubert; their marriage lasted a year. Saint James had a son, Harmony Lucas, and a daughter, Sunshine Lucas, with second husband Tom Lucas. She married Lucas, a makeup artist, sometime in the 1970s, but the marriage did not last.

When guest-hosting the venerable NBC sketch comedy series Saturday Night Live in 1981, Saint James met her future third husband, then-SNL executive producer (and now president of NBC Sports) Dick Ebersol. They hit it off immediately and married within the year. The marriage produced three children, Charles, Willie, and Teddy (deceased). In 2002, Saint James filed for divorce, but the couple reconciled later that same year.

Saint James has stated that she has returned to Catholicism following her estrangement, in part, because "It's the only way I know how to pray."

Saint James is a recovering alcoholic.

On November 28, 2004, a plane carrying Ebersol and two of their boys crashed in Colorado; although Ebersol and their oldest son Charles survived the crash, their 14-year-old son Teddy was killed.