Howard Waldrop was born in Houston, Mississippi on September 15, 1946, and moved to the Dallas-Fort Worth area of Texas in 1950. He attended the University of Texas at Arlington, spent two years in the Army, and lived briefly in Grand Prairie and Bryan before moving to Austin in 1974 where he was been a member of the well-known Turkey City Writers Workshop along with Bruce Sterling, Leigh Kennedy, Chad Oliver, Lewis Shiner, and others.

Waldrop spent most of his life in Texas, especially in the Austin area. A prolific and singular writer, he was once described by George R. R. Martin as "the most startling, original, and entertaining short story writer in science fiction today."

He sold his first story to Analog, entitled "Lunchbox", in 1972, and was subsequently widely published in places as diverse as Omni, Playboy, Universe, Crawdaddy, New Dimensions, Shayol, Orbit, and Zoo World. His first novel, The Texas Israeli War: 1999, written in collaboration with fellow Texan Jake Saunders, was published in 1974. In 1984 his solo novel, Them Bones, was published as part of the new Ace Specials line. But it was as a short story writer that Waldrop made his reputation. Many of his unique and bizarre stories have been published in different collections, including Howard Who? (1986), All About Strange Monsters of the Recent Past (1987), Custer's Last Jump and Other Collaborations (2003), and H'ard Starts: The Early Waldrop (2023). A particularly notable collection of his stories, Night of the Cooters (the title story was a 1988 Hugo nominee, and was adapted into an animated short in 2022), was published in 1990.

His 1980 story "The Ugly Chickens" won both the Nebula and World Fantasy Awards in 1981, and Waldrop has also been frequently nominated over the years for many other awards, including the Hugo, the Nebula, the Locus, the Balrog, and the Sidewise Awards. In the course of his long career, Waldrop wrote over two hundred stories, with his most recent one (not including those appearing only in a collection) being "Til the Cows Come Home To Roost", in the Spring 2018 issue of Lady Churchill's Rosebud Wristlet He received the World Fantasy Award for Life Achievement in 2021.

Waldrop died from a stroke in Austin, on January 14, 2024, at the age of 77.