Donald Barthelme was born in Philadelphia in 1931 to parents Donald Barthelme Sr. and Helen (Bechtold) Barthelme. In 1932, the family moved to Houston, where Donald Barthelme Sr. developed an architectural practice and taught at the University of Houston and Rice University. Barthelme had four younger siblings: Joan (born 1932), Peter (born 1938), Frederick (born 1943), and Steven (born 1947).
Barthelme enrolled at the University of Houston in 1949, where he took courses in journalism, literature, creative writing, and philosophy. He became a reporter, critic, and editor for the school's newspaper, The Cougar.
In July 1951, he left the University of Houston for a job at the Houston Post, where he reviewed movies, plays, and concerts. From July 1953 to December 1954 he served in Korea, writing for the 2nd Infantry Division's official publication. Following his return to Houston, Barthelme took a public relations job at the University of Houston. There he founded and became editor of the interdisciplinary journal Forum. In 1961, Barthelme became acting director of the Contemporary Arts Museum. The following year he moved to New York City to edit a new journal of art and literature called Location.
In 1961, Barthelme's short story "The Darling Duckling at School" (later renamed "Me and Mrs. Mandible") appeared in the journal Contact. Inspired by Samuel Beckett, Barthelme rejected the constraints of traditional plot, setting, and character development in favor of verbal collages full of absurdity and wit. In 1963, Barthelme published the story "L'lapse" in the New Yorker, quickly becoming a regular contributor.
In 1964 Barthelme released his first collection of stories, Come Back, Dr. Caligari. From that point on, he stayed at the forefront of American literature for three decades. Barthelme published nine more story collections, and 129 stories and "casuals" in the New Yorker. Always innovative, he created "collage stories" that combined images and text, and "dialogue stories" in which two disembodied voices alternate in conversation. He also published three novels - Snow White, The Dead Father, and Paradise. In 1972 he released a children's book, The Slightly Irregular Fire Engine, winning the National Book Award for Children's Literature.
Barthelme remains best known for Sixty Stories, a 1981 anthology of his finest work from the sixties and seventies. Sixty Stories was nominated for the National Book Critics Circle Award, the PEN/Faulkner Award for Fiction, and the Los Angeles Times Book Prize in 1982.
Donald Barthelme taught creative writing at City College in New York from 1974-75. In 1979, he was invited to teach in the Creative Writing Program at the University of Houston. Initially he taught in Houston one semester a year, while continuing to live in New York City. In 1983, Barthelme moved to Houston to become a full-time professor. A beloved teacher, he eventually became director of the Creative Writing Progam, a position he held until his death.