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.

Dubus's life was scarred 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. In his essay "Giving up the Gun", published in The New Yorker, Dubus describes that night as the point at which he decided to stop arming himself and to take a less hostile and defensive view of life.

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 physical pains imposed by his condition, and with clinical depression. Over the course of his struggles Dubus's third wife left him, taking their two young daughters.

To help Dubus with his mounting medical bills, his friends and fellow writers, Kurt Vonnegut and John Updike held a special literary benefit. Dubus was extremely grateful, and his appreciation extended to holding workshops and reading sessions for aspiring writers. Despite these physical, psychological, and emotional difficulties, Dubus continued to write, producing two books of essays and a collection of short stories. He also conducted a weekly writers' workshop in his home, meeting with a group of young writers, many of whom were teenage girls in a residential program for abused adolescents.

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, personal level. Those who knew him admired the peace and acceptance he had achieved, as well as his ability to live his life without bitterness or self-pity.

Dubus spent his later years in Haverhill, until his death from a heart attack in 1999, at age 62. He is buried in Elmwood Cemetery in Bradford, Massachusetts, which is part of Haverhill. 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. The novel was later filmed.