[3] F2M, a play she authored, was performed in 2011 as part of the New York Stage and Film and Vassar College's 2011 Powerhouse Theater season.

Later that year, she made her big screen debut in the drama film Guilty by Suspicion starring opposite Robert De Niro and Annette Bening.

[11] Wettig has starred in a number of made-for-television movies, include Taking Back My Life: The Nancy Ziegenmeyer Story (1992) and Parallel Lives (1994).

From 2002 to 2004, she played the recurring role of CIA psychotherapist Dr. Judy Barnett on Alias (on which her husband was an executive producer and director).

From 2005 to 2007, Wettig appeared in 18 episodes of Fox television drama, Prison Break, playing fictional Vice President Caroline Reynolds.

[14] In 2014, she starred in the unsold the CW drama pilot Identity opposite Ahna O'Reilly[15] In 2019, she played a leading role in the episode of Netflix anthology series Heartstrings.

[16] In 2020, ABC ordered a sequel for Thirtysomething and Wettig set to return alongside Olin, Timothy Busfield and Mel Harris.