Wettig, one of three sisters, was born in Cincinnati, Ohio to Florence Morlock and Clifford Neal Wettig, a college basketball coach. She attended Ohio Wesleyan University and graduated from Temple University in 1975. She recently returned to her studies, receiving an M.A. in playwriting from Smith College in 2001; a field which she is now concentrating on. Wettig is married to actor and producer Ken Olin; they have two children, Clifford (b. 1983) and Roxanne (b. 1986).

Although Wettig has acted in a number of feature films (including City Slickers, Guilty by Suspicion, and The Langoliers), she is best known for her work on television. In particular, she received critical acclaim (and a number of awards) for her role as Nancy Weston on ABC's thirtysomething. She also portrayed Joanne McFadden on the television program St. Elsewhere. In addition, Wettig appeared in a number of popular television programs during the 1980s and 1990s including L.A. Law, Frasier, Hill Street Blues, and Remington Steele.

Wettig is a featured cast member in the series Brothers & Sisters, which debuted in September 2006, where she portrays the Walker family's patriarch's mistress, Holly Harper. Wettig also had the recurring role of CIA psychotherapist Dr. Judy Barnett on Alias, which was produced and directed by her husband and former thirtysomething co-star Ken Olin. Before joining Brothers & Sisters, she played Caroline Reynolds on the Fox television drama, Prison Break.