Sedaris has appeared in various films, including Maid in Manhattan (2002), School of Rock (2003), Elf (2003), Bewitched (2005), Chicken Little (2005), Shrek the Third (2007), Jennifer's Body (2009), Puss in Boots (2011), Chef (2014), Ghost Team (2016), Handsome (2017), The Lion King (2019), and The Boss Baby: Family Business (2021).

[4][5] Her parents were Sharon Elizabeth (née Leonard), a homemaker, and Louis Harry "Lou" Sedaris, an IBM engineer.

[15][11] When she was four, her family moved to Raleigh, North Carolina, where she grew up with her five siblings: Lisa, David, Gretchen, Tiffany, and Paul.

[19] In her brother David's book Me Talk Pretty One Day, he noted that she would often assume characters to play pranks on her family.

During that time, she was dating a man from Greece, and one evening after coming home from cooking, she found him unconscious on the kitchen floor.

[15] Sedaris's first major foray into television began in 1995 on the Comedy Central sketch series Exit 57; alongside Colbert and Dinello.

(2001), Sex and the City (2002–2003), Monk (2002–2003), Wonder Showzen (2005), My Name Is Earl (2006), Sesame Street (2006), Rescue Me (2007), The Closer (2009), The New Adventures of Old Christine (2009), The Middle (2010), Raising Hope (2011–2014), and The Good Wife (2012).

In 2008, Sedaris starred as Principal Abby Hofman in the Nickelodeon television film Gym Teacher: The Movie, which was directed by her Strangers with Candy co-star and frequent collaborator Paul Dinello.

In early 2010, she had a supporting character in the Canadian comedy series The Drunk and On Drugs Happy Fun Time Hour.

Grey Global Group designed the commercials as "kicking the old 'mom' image with spots featuring 'laundry expert' (and accomplished lifestyle guru) Amy Sedaris".

[30] In 2013, she replaced Kristen Schaal as the sex-crazed Hurshe Heartshe, in the second season of the Adult Swim comedy series The Heart, She Holler.

[31] That same year, Sedaris appeared in a major recurring role in the Amazon Prime Video political satire series Alpha House, which was written by Doonesbury creator Garry Trudeau.

Sedaris had a starring role as Janice Delongpre, a dispatch officer, in the CBS All Access comedy series No Activity from 2017 to 2019.

Sedaris has voiced commercials for the discount hair salon chain Supercuts[34][35] and was WordGirl character Miss Davis for two seasons.

[36] She narrated the PBS special Make 'Em Laugh: The Funny Business of America, a six-hour documentary on comedians and comedy in American history.

From 2014 to 2020, she provided the voice for Princess Carolyn in the Netflix adult animated comedy series BoJack Horseman, a role which some critics consider her best work.

In a 2006 interview with the magazine, she answered part of a Q&A section with, "TURN-OFFS: The beach, having to pay for things, racist people, Orientals.

While promoting her book on Late Night with David Letterman in October 2010, she demonstrated how the cover can easily be made into a hat.

[citation needed] Amy has co-written several plays with her brother David, credited only as "The Talent Family": Stump the Host (1993), Stitches (1994), One Woman Shoe (1995), Incident at Cobblers Knob (1997), and The Little Frieda Mysteries (1997).

She had a role in David Lindsay-Abaire's play Wonder of the World and the stage adaptation of her book Wigfield (2003), alongside Paul Dinello and Stephen Colbert.