Sedaris grew up in Raleigh, N.C., the second oldest of six siblings; his sister Amy also became a noted humorist. In 1977 he dropped out of Kent State University (Ohio) to hitchhike around the United States. On the road, he took several unusual jobs and started writing a diary on placemats in diners. While attending the School of the Art Institute of Chicago (1985–87), Sedaris began reading his diaries at a local club, and he eventually was invited to read them on the city's public radio station.

In his next book, Dress Your Family in Corduroy and Denim (2004), Sedaris, by elucidating with a surgeon's skill the countless gaps and crossed wires in each interaction he described, demonstrated once again the hilarious absurdity lurking beneath the veneer of ordinariness. His recording of pieces from the book was nominated for a Grammy Award for best spoken-word album, and David Sedaris: Live at Carnegie Hall (2003) received a Grammy nomination for best comedy album. In 2005 Sedaris edited Children Playing Before a Statue of Hercules, an anthology of stories from his favourite authors. Allegations that he had exaggerated or even fabricated some of his nonfiction works surfaced in 2007 but had little negative impact on Sedaris, who was already being compared to Mark Twain (Twain, Mark), James Thurber (Thurber, James), and Dorothy Parker (Parker, Dorothy). In 2008 he published his sixth essay collection, When You Are Engulfed in Flames.