Andre Dubus was born in Lake Charles, Louisiana, the oldest child of a Cajun-Irish Catholic family. His surname is pronounced "Duh-BYOOSE", with the accent on the second syllable to rhyme with the noun "excuse." Dubus grew up in the Bayou country in Lafayette, Louisiana, and was educated by the Christian Brothers, a Catholic parochial school that emphasized literature and writing. Dubus graduated from nearby McNeese State College in 1958 as a journalism and English major. Dubus then spent six years in the Marine Corps, eventually rising to the rank of captain. At this time he married his first wife and started a family. After leaving the Marine Corps, Dubus moved with his wife and four children to Iowa City, where he later graduated from the University of Iowa's Iowa Writers' Workshop with an MFA in creative writing, studying under Richard Yates. He admired Hemingway, Chekhov, and Cheever.

Dubus's life was marked by tragedy. His sister was raped as a young woman, causing Dubus many years of paranoia over his loved ones' safety. Dubus carried personal firearms to protect himself and those around him, until the night in the late 1980s, when he almost shot a man in a drunken argument outside a bar in Tuscaloosa, Alabama.

Dubus experienced a personal tragedy late on the night of July 23, 1986, when he was seriously injured in a car accident. He was driving from Boston to his home in Haverhill, Massachusetts, and he stopped to assist two disabled motorists...brother and sister Luis and Luz Santiago. As Dubus assisted the injured Luz to the side of the highway, an oncoming car swerved and hit them. Luis was killed instantly; Luz survived because Dubus had pushed her out of the way. Dubus himself was critically injured. As a result of the accident, both Dubus's legs were crushed. His left leg had to be amputated above the knee, and Dubus would eventually lose the use of his right leg. Dubus would spend three painful years undergoing a series of operations, and extensive physical therapy. Despite his efforts to walk with a prosthesis, chronic infections confined him to a wheelchair for the remainder of his life. Dubus continued to battle the pain imposed by his condition, and with clinical depression. Over the course of these struggles Dubus's third wife left him, taking with her their two young daughters.

To help Dubus with mounting medical bills, Andre's friends and fellow writers, Kurt Vonnegut and John Updike held a special literary benefit. Dubus continued to write, producing two books of essays and a collection of short stories, and conducted a weekly writers' workshop in his home, meeting with a group of young writers.

Dubus also found a deeper religious faith at this time. A practicing Catholic all his life, Dubus found that the loss of his mobility drew him closer to God, and renewed his Catholic faith at a deeper level.

Dubus spent his later years in Haverhill, until his death from a heart attack in 1999, at age 62. He is buried in Greenwood Cemetery, near where he lived, in Haverhill, Massachusetts. He married three times, and fathered six children. His son Andre Dubus III is also an author, whose most noteworthy book is the novel House of Sand and Fog (1999), a finalist for the National Book Award.

Although he did write one novel, The Lieutenant, in 1967, Dubus considered himself primarily as a writer of short fiction. Throughout his career, he published most of his work in small, distinguished literary journals such as Ploughshares and Sewanee Review. Later in his career he placed stories in magazines such as The New Yorker and Playboy. Andre remained loyal to a small publishing firm run by David R. Godine that published his first works. When larger book publishers approached him with more lucrative deals, Dubus stayed with Godine, switching only to Alfred A. Knopf towards the end of his career to assist with medical bills.

Dubus's collections include: Separate Flights (1975), Adultery and Other Choices (1977), Finding a Girl in America (1980), The Times Are Never So Bad (1983), Voices from the Moon (1984), The Last Worthless Evening (1986), Selected Stories (1988), Broken Vessels (1991), Dancing After Hours (1996), and Meditations from a Movable Chair (1998). His writing awards include the PEN/Malamud, the Rea Award for the Short Story for excellence in short fiction, the Jean Stein Award from the American Academy of Arts and Letters, and fellowships from the Guggenheim and MacArthur Foundations. Several writing awards are named after Dubus. His papers are archived at McNeese State University and Xavier University in Louisiana.

After Dubus's death, his story "Killings" was adapted into Todd Field's In the Bedroom (2001) starring Sissy Spacek, Tom Wilkinson, and Marisa Tomei . The film was nominated for five Academy Awards — Best Picture, Actor in a Leading Role (Wilkinson), Actress in a Leading Role (Spacek), Actress in a Supporting Role (Tomei), and Best Writing, Screenplay Based on Material Previously Published (Robert Festinger & Field).

The 2004 movie, We Don't Live Here Anymore is based upon two of Dubus' novellas, "We Don't Live Here Anymore" and "Adultery."