Her initial film role was a bit part in the family comedy Uncle Buck (1989), starring John Candy and her eventual My Girl co-star Macaulay Culkin.

After college, she was hired as a fact-checker for the Zagat Survey and moved to New York City,[11] which was followed by a position as an editorial assistant for a HarperCollins science fiction-fantasy imprint.

[18] In addition to her role on Veep, Chlumsky has appeared in multiple television series between 2011 and 2013, including White Collar, Law & Order: Special Victims Unit, and NBC's adaptation of Hannibal.

Chlumsky has appeared on Broadway in You Can't Take It with You, and beginning in 2015 as editor Iris Peabody in the comedy Living on Love, with Renee Fleming, Jerry O'Connell and Douglas Sills.

In 2017, Chlumsky appeared in the fourth season of AMC Networks' Halt and Catch Fire as Dr. Katie Herman, the love interest of Gordon Clark (Scoot McNairy).

[19] Chlumsky had a main role alongside Julia Garner in Shonda Rhimes' Netflix limited drama series Inventing Anna.

[21] In October 2007, Chlumsky announced her engagement to Army Reserve member Shaun So,[22] who served a tour of duty in Afghanistan.