A former member of Chicago-based Second City and Annoyance Theatre comedy troupes, Sedaris' first major foray into television began in 1995 on the Comedy Central sketch show Exit 57. Beginning in 1999, Sedaris portrayed Jerri Blank in the Comedy Central series Strangers with Candy, which ran for three seasons and would later inspire a full-length movie.
Sedaris has made numerous guest appearances on a number of different TV programs, including Rescue Me, Monk, Wonder Showzen, Just Shoot Me!, Sex and the City, My Name Is Earl, The Closer, The Middle, The New Adventures of Old Christine, Raising Hope, and Sesame Street. She also hosted the series Film Fanatic.
In January 2009, Sedaris narrated the PBS special Make 'Em Laugh: The Funny Business of America, a six-hour documentary on comedians and comedy in American history. In early 2010, she appeared as a supporting character in the Canadian comedy series The Drunk and On Drugs Happy Fun Time Hour. From September 2010 to February 2011, she voiced Miss Davis in WordGirl.
In 2013, Sedaris appeared in eight episodes of Amazon's Alpha House, a political comedy series written by Doonesbury creator Garry Trudeau. Since 2014, she has provided the voice for Princess Carolyn on the Netflix original series BoJack Horseman.
Sedaris has also had small roles in a number of films, including Elf, School of Rock, Maid in Manhattan, Bewitched, Snow Angels, Full Grown Men, Old Dogs, Shrek the Third, Chicken Little, and Shrek Forever After, and in television shows such as Star vs the Forces of Evil and BoJack Horseman.
- Amy voices Princess Carolyn in the animated Netflix series "BoJack Horseman".
- She also voices Lydia and Mina Loveberry in the animated Disney XD series "Star vs. the Forces of Evil".