Sedaris was born in Endicott, New York, the daughter of Sharon (née Leonard) and Lou Sedaris, and grew up in Raleigh, North Carolina, with her siblings, Lisa, David, Gretchen, Tiffany, and Paul ("The Rooster"). She is of half Greek descent; her father isGreek Orthodox and her mother was Protestant. She remains Greek Orthodox.
As a guest on the Late Show with David Letterman, she described two experiences with bosses. At age 16, she worked at the localWinn-Dixie supermarket. She would make fake announcements over the loudspeaker, which prompted the head cashier to confiscate the microphone. After work, she egged the cashier's car in protest. Later, as a cocktail waitress at Zanies, a comedy night club in Chicago, she was five minutes late for a shift with ice cream cone in hand. Fired that night, she took her revenge on her boss: "I took his keys and I threw them in the snow. I heard he found them in the spring."
Sedaris and her Strangers with Candy co-star Paul Dinello dated for eight years. Though their relationship ended, they have remained very close friends and Dinello made Sedaris godmother to his son. Sedaris has never married, and has stated in several interviews that she has never wanted to marry or have children.
It was announced in October 2008 that Sedaris would be getting her own sitcom, produced by 20th Century Fox, which she will be creating, writing and starring in. Also in late 2008, Sedaris did voiceovers in several commercials for the discount hair salonSuperCuts.
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.
From September 2010 to February 2011, she also voiced the WordGirl character Miss Davis, the Woodview School's debate club teacher in the season 2 episode "Cleanup on Aisle Eleven" and where she was the schoolteacher of Becky, Todd, Violet, Tobey and Victoria in "Cherish is the Word" in season 3.
In December 2010, Sedaris was seen with Paul Dinello in the "Mummified Hand" episode of the Discovery/Science Channel showOddities.
In 2011, she appeared in a series of commercials for Downy Unstopables, a fabric softener product. The ad was designed by Greywith the aim of "kicking the old 'mom' image with spots featuring 'laundry expert' (and accomplished lifestyle guru) Amy Sedaris".
In 2013, Sedaris appeared in eight episodes of Amazon's Alpha House, a political comedy series written by Doonesbury creatorGarry Trudeau. Sedaris played Louise Laffer, the Mormon wife of Utah Senator Louis Laffer, who lives with three other Republican senators in a town house on Capitol Hill.
At a book signing for her 2010 bookSimple Times: Crafts for Poor People
She coauthored the text-and-picture novel Wigfield with Paul Dinello and Stephen Colbert, published in 2003. As of 2005, Sedaris writes a monthly advice column in The Believer. She has written a guide to entertaining titled I Like You: Hospitality Under the Influence, published in October 2006 by Warner Books. That light-hearted approach to cooking stayed on the New York Times bestseller list for more than 12 weeks, and currently has over 350,000 copies in print.
Her book, Simple Times: Crafts for Poor People! (2010), included a cover that can be easily made into a hat, as David Letterman demonstrated during her appearance on hisLate Show in October 2010.
Along with her brother David Sedaris, Amy has co-authored several plays under the name "The Talent Family": Stump the Host (1993), Stitches (1994), One Woman Shoe (1995), Incident at Cobblers Knob (1997) andThe Little Frieda Mysteries. She also co-authored the play The Book of Liz with him, which has gone on to productions at such regional theaters as No Name Players.
Her theater work includes a role as the stage manager in Paul Rudnick's play The Most Fabulous Story Ever Told.
In support of PETA's anti-fur campaign, Sedaris appeared as her Strangers with Candy character in an ad that reads, "When you wear fur, people laugh at you, not with you."
In addition to acting and writing, she ran a cupcake and cheese ball business, Dusty Food Cupcakes, out of her home kitchen,but has since ceased doing so.
She was the emcee for Microsoft's 2010 annual employee meeting at Safeco field in Seattle, Washington, on September 28, 2010.