Born and raised in Queens, DeWitt developed a love of performing at an early age. As a first grader, she acted in school plays such as "The Feel" and "The Circus," though she continually tried to dissuade herself from pursuing it seriously. It was during high school that she happened to catch Frances McDormand and Blythe Danner in a Broadway production of "A Streetcar Named Desire" and slowly began to warm to the idea of acting professionally. DeWitt went on to major in creative studies at New York's New College at Hofstra University, and by the time she saw a stage production of "Angels in America," she had shed all doubts as to what her career path would be. To further prepare herself, she began honing her skills at the city's The Actor's Center.
In June of 2000, DeWitt cut her teeth on her first off-Broadway performance, appearing as Michaela in Glenn Meizer's "Anonymous," at the McGinn/Cazale Theatre. That year, she also had landed her first feature film role in Matthew Coppola's drama "Fresh Cut Grass" (2000). A year later, she made a foray into television with an appearance on NBC's "Law & Order: Special Victims Unit" (1999- ). DeWitt did a run at the Atlantic Theater in October of 2002 in George S. Kaufman's "The Butter and Egg Man," as the fetching assistant Jane Weston, and was now juggling stage and screen work with ease. Her episode of "Queens Supreme" (CBS, 2003) failed to make it to air when the sitcom was cancelled in January, but by mid-year, DeWitt was back on television screens, appearing on HBO's "Sex and the City" (1998-2004). The episode also, coincidentally, featured her future "Standoff" co-star Ron Livingston as Berger, Carrie Bradshaw's (Sarah Jessica Parker) then current onscreen beau.
DeWitt's New York acting career was moving right along. In March 2004, she was back on the Manhattan stages as Fanny in Craig Lucas' "Small Tragedies." She and her castmates would win OBIE Awards for their performances. That month, she also began shooting another feature film, The Great New Wonderful (2006), a drama about post-9/11 anxieties. In April, DeWitt's career made a life-altering leap when she began shooting her role as Renee Zellweger's neighbor Sara Wilson in Ron Howard's Depression drama, Cinderella Man (2005). Howard agreed to audition DeWitt after having learned of her connection to the film - that she was, in fact, the great-granddaughter of the film's subject, boxing hero James J. Braddock. Later that year, she returned to her first love at the Second Stage Theatre as the hardened, but vulnerable Roberta in John Patrick Shanley's "Danny and the Deep Blue Sea."
In 2005, DeWitt become a leading lady of television, top-lining CBS' dramatic pilot "The Commuters" as one of three married suburban couples. Though the pilot was completed, the series failed to make the network's lineup. In June, her role as the mother of lead character Chelsea in another New York-based film, Antonio Campos' "Buying the Cow" (2005), was seen by international audiences at the Cannes Film Festival. A month later, DeWitt landed a two-episode stint as Heather on FX's gritty drama, "Rescue Me" (2004-2011). Back at home, she jumped back into more films, first with the independent comedy "Shut Up & Sing" (2006), followed by playwright Kenneth Lonergan's second filmed effort, Margaret (2011) and Off the Black (2006), an independent coming of age drama.
By the start of 2006, DeWitt had been cast as a lead in the "Standoff" pilot, a part she won while visiting Los Angeles for pilot season auditions. She and co-lead Ron Livingston - best known for his work in "Swinger" (1996) and "Office Space" (1999) - shot the pilot in mid-March and by April, a very in-demand DeWitt was back on the small screen, guest-starring on CBS' short-lived "Love Monkey" (2006) and playing Midge, the sometimes lover of Don Draper (Jon Hamm) on AMC's "Mad Men." When "Standoff" (2006-07) made the network's cut, rabid New Yorker DeWitt moved to Los Angeles to tape the show's first season. Airing on Fox, DeWitt's banter-heavy scenes with Livingston sizzled and made her an instant viewer favorite. But there were not enough viewers to sustain the show in the ratings, which led to the network canceling the series after only one season. Meanwhile, she co-starred in Jonathan Demme's comic drama, Rachel Getting Married (2008), playing a sister whose troubled sibling (Anne Hathaway) comes home for her wedding, which reveals deep-rooted tensions in the family. For her work, DeWitt earned an Independent Spirit Award nomination for Best Supporting Female, as well as a slew of critic awards nominations.
From there, DeWitt co-starred in the indie comedy "Tenure" (2009) and was Ben Affleck's concerned wife in The Company Men (2010), John Wells' character drama about several white-collar employees struggling to rebuild their lives after downsizing during a recession. Back on the small screen, she was the self-absorbed younger sister of a wife and mother (Toni Collette) with multiple personality disorder on the acclaimed comedy series "The United States of Tara" (Showtime, 2009-2011). At the same time, her career collided with her personal life when she married "Standoff" co-star Ron Livingston in 2009. DeWitt managed to avoid being scathed by the universally panned romantic comedy, A Little Bit of Heaven (2012), starring Kate Hudson and Gael García Bernal, and fared slightly better with the charming, but overly sentimental fantasy The Odd Life of Timothy Green (2012). Meanwhile, DeWitt found herself to be the recipient of widespread critical acclaim once again, this time for her supporting turn in the comic indie drama Your Sister's Sister (2012), where she played the lesbian sister of a woman (Emily Blunt) who takes up with her dead ex-boyfriend's brother (Mark Duplass). Her performance was hailed by most critics and earned her an Indie Spirit Awards nod for Best Supporting Actress.