DeWitt played Emily Lehman in the Fox television series Standoff (2006–07), co-starring with her future husband Ron Livingston, as well as Charmaine Craine on United States of Tara.

DeWitt appeared in the indie-thriller Sweet Virginia, directed by Jamie Dagg, which premiered at the 2017 Tribeca Film Festival.

In addition to her role on United States of Tara, DeWitt also recurred on the AMC series Mad Men, playing Midge Daniels, Don Draper's (Jon Hamm) bohemian mistress, in the show's first season.

[11] Most notably, she starred in John Patrick Shanley's Danny and the Deep Blue Sea at the Second Stage Theatre;[7] George S. Kaufman's The Butter and Egg Man at the Atlantic Theater Company;[7] and Craig Lucas' Small Tragedy, for which the entire cast won an Obie Award.

[7] From May 4–23, 2010, DeWitt appeared in MCC Theater's Off Broadway play Family Week, written by Beth Henley and directed by Jonathan Demme.