Born in Alberta, Louisiana, a sawmill town,Brown grew up in Ouachita County, Arkansas, which experienced an oil boom when he was thirteen. Brown's mother later relocated to Little Rock so he and his brother and two sisters could attend a better high school. The public library became his second home. Reading the three-volume History of the Expedition under the Command of Captains Lewis and Clark helped him develop an abiding interest in the American West. He also discovered the works of Sherwood Anderson and John Dos Passos, and later William Faulkner and Joseph Conrad. He cited these authors as those most influential on his own work.

While attending home games by the Arkansas Travelers baseball team, he became acquainted with Moses Yellowhorse, a pitcher. His kindness, and a childhood friendship with a Creek boy, caused Brown to reject the portrayals of Indian peoples as violent and backward, which dominated American popular culture at the time.

He worked as a printer and reporter in Harrison, Arkansas, and decided to continue his education at Arkansas State Teachers College in Conway, Arkansas. His mentor, history professor Dean D. McBrien, helped set him on the road to becoming a writer. They traveled west along with other students on two occasions in a Model T Ford. On campus Brown worked as editor of the student newspaper and held a student assistantship in the library. The latter convinced him that he should become a librarian. So, in the middle of the Depression, he set out for George Washington University in Washington, D.C. He worked part-time for J. Willard Marriott, took classes, and married Sally Stroud (another graduate of Arkansas State Teachers College drawn to Washington by the New Deal). Eventually he found a full-time position and became a librarian for the U.S. Department of Agriculture from 1934 to 1942.

Brown's first novel was a satire of New Deal bureaucracy, but it was not published due to the bombing of Pearl Harbor. The publisher suggested "something patriotic" instead. He responded with Wave High the Banner, a fictionalized account of the life of Davy Crockett (who was an acquaintance of his great-grandfather). A few months after its publication, he was drafted into the U.S. Army where he met Martin Schmitt; after the war they collaborated on several works.

During the war, Brown never went overseas, and worked for the United States Department of War as a librarian. From 1948 to 1972, he was an agriculture librarian at the University of Illinois at Urbana-Champaign, where he had gained a master's degree in library science, became a professor, and raised a son, Mitchell, and daughter, Linda. As a part-time writer, he published nine books, three fiction and six nonfiction, by the end of the 1950s. During the 1960s, he completed eight more including The Galvanized Yankees, which Brown described as requiring more research than any of his other books and The Year of the Century: 1876, which he described as his personal favorite.

In 1971 Bury My Heart at Wounded Knee became a best-seller. Many readers assumed that Brown was of Indian heritage but, in fact, he was not. He did however come from a family with deep frontier history.

In 1973, he retired in Little Rock, Arkansas and devoted his time to writing. His later works include Creek Mary's Blood, a novel telling of several generations of a family descended from one Creek woman, and Hear That Lonesome Whistle Blow, which described the chicanery and romance surrounding the construction of the western railroads. His last book-length work, Way To Bright Star is a picaresque novel set during the Civil War. He never completed its sequel, which was to feature P. T. Barnum and Abraham Lincoln.

Brown died at the age of 94 in Little Rock, Arkansas. His remains are interred in Urbana, Illinois, along with those of Sally Stroud. The Central Arkansas Library System named a branch library in Little Rock, Arkansas for him.

Histories

• Fighting Indians of the West (1948) with Martin F. Schmitt
• Trail Driving Days (1952) with Martin F. Schmitt
• Grierson's Raid (1954) Describes a Union foray into Confederate territory
• Settlers' West (1955) with Martin F. Schmitt
• The Gentle Tamers: Women of the Old Wild West (1958)
• The Bold Cavaliers: Morgan's Second Kentucky Cavalry Raiders (1959) Republished as Morgan's Raiders (1995). Describes John Hunt Morgan's Civil War activities.
• The Galvanized Yankees (1963) Republished (1986)
• Showdown at Little Big Horn (1964) For young people
• The Year of the Century: 1876 (1966)
• Bury My Heart at Wounded Knee (1970)
• Fort Phil Kearny: An American Saga (1971) Republished as The Fetterman Massacre (1974)
• Andrew Jackson and the Battle of New Orleans (1972)
• The Westerners (1974)
• Hear That Lonesome Whistle Blow (1977)...about the Union Pacific Railroad
• Wondrous Times on the Frontier (1991)
• The American West (1994) Collected excerpts from earlier books co-authored by Schmitt
• Great Documents in American Indian History (1995)

Novels

• Wave High The Banner (1942)
• Yellowhorse (1956)
• Cavalry Scout (1958)
• They Went Thataway (1960) republished as Pardon My Pandemonium (1984)
• The Girl from Fort Wicked (1964)
• Action at Beecher Island (1967)
• Creek Mary’s Blood (1980)
• Killdeer Mountain (1983)
• Conspiracy of Knaves (1986) A Civil War historical saga and spy thriller
• Way To Bright Star (1998)

Other

• Tales of the Warrior Ants (1973) For young people
• American Spa: Hot Springs, Arkansas (1982) An illustrated history
• Dee Brown's Folktales of the Native American: Retold for Our Times (1993) Originally published as Teepee Tales (1979)
• When the Century Was Young (1993) Memories of growing up in 1920s & 1930s
• Images of the Old West (1996)