Sela Ward, the eldest of four children, was born in Meridian, Mississippi, the daughter of Annie Kate and Granberry Holland Ward, Sr. She attended the University of Alabama in Tuscaloosa, where she performed as one of the Crimson Tide cheerleaders, was homecoming queen, joined Chi Omega sorority, and double-majored in art and advertising.

While working in New York City as a storyboard artist for multimedia presentations, the 5'7" (170cm) Ward began modeling to supplement her income. She was recruited by the Wilhelmina agency and was soon featured in television commercials promoting Maybelline cosmetics. Ward eventually moved to California to pursue acting and landed her first film role in the Burt Reynoldsvehicle, The Man Who Loved Women, released in 1983. Her first regular role in a television drama series (as a beautiful socialite on Emerald Point, NAS) followed in the same year. Ward subsequently played variations on the same character in films and television guest spots throughout the 1980s, most notably opposite Tom Hanks in 1986's Nothing in Common. This pattern persisted until she aggressively pursued and won the role of the bohemian alcoholic Teddy Reed on Sisters, for which she received her first Emmy for Outstanding Lead Actress in a Drama Series in 1994.

Ward also won a CableACE Award for her portrayal of the late television journalist Jessica Savitch in the 1995 TV movie Almost Golden: The Jessica Savitch Story. A 39-year-old Ward was passed over for a Bond girl role, learning that even though then-Bond Pierce Brosnan was 42, the casting director said "What we really want is Sela, but Sela ten years ago". In response, she developed and produced a documentary, The Changing Face of Beauty, about American obsession with youth and its effect on women.

Ward succeeded actress Candice Bergen as commercial spokesperson for Sprint's long distance telephone service from 1999 until 2002, when landline long distance promotions fell out of favor. She also appeared on Frasier as supermodel/zoologist Kelly Easterbrook in the fifth season opener ("Frasier's Imaginary Friend"). When she read for the role of Lily Brooks Manning on the series Once and Again, its creators initially deemed Ward "too beautiful" for the average single mother to identify with. After landing the part, she received her second lead actress Emmy and a Golden Globe Award for her efforts.

In 2004 she played the role of a private investigator, Bobbi Bacha of Blue Moon Investigations, in the TV movie Suburban Madness, the story of a dentist who ran over her cheating orthodontist husband with her Mercedes. In 2005, she began a recurring role in the Fox dramatic series House as Stacy Warner, the hospital's former attorney, who also happens to be the ex-partner of the protagonist, Dr. Gregory House.

Ward was originally offered the role of Megan Donner on CSI:Miami and Susan Mayer on Desperate Housewives, but turned both down. The parts later went to Kim Delaney and Teri Hatcher respectively. Ward says she does not want another lead role in an hour-long series due to the time away from her family it would require. She developed and produced a pilot for a half-hour situation comedy (in which she would also star) for CBS' 2006 season but it was not selected by the network for its roster.

In 2002, Ward published her much anticipated autobiography, Homesick: A Memoir, through HarperCollins' ReganBooks imprint.