DeBow was born in Charleston, South Carolina in 1820 and moved to New Orleans as a young man. It was in that city that he founded the popular DeBow's Review, a periodical focused on business and the economy. In 1848, he was named a professor of commerce and statistics at the University of Louisiana (now Tulane). Later that year, he was appointed head of the newly created Bureau of Statistics of the State of Louisiana.

Although Joseph C.G. Kennedy, a Whig, had planned and collected results from the 1850 census, he did not continue as superintendent when the 1852 presidential election removed his party from power. The incoming president, Franklin Pierce, appointed DeBow superintendent of the census, a position he held from 1853 to that census’s completion in 1855. DeBow published the census results, probably using some of Kennedy’s material, and a summarized version that came to be known as the Compendium, which was very popular for the time. His Statistical View of the United States is considered by some to be a groundbreaking publication in economic statistics. In the introduction to the Compendium, DeBow included the first map to be published by the Census Office. The report also contained several recommendations that would not be realized until some 50 years later – including the suggestion of a permanent census office. It also urged the use of trained, professional, enumerators instead of inexperienced workers appointed on the basis of political patronage.

During the Civil War, DeBow supported the Confederacy; in his publications he continued his long-established campaign to encourage Southerners to diversify their economic interests. He urged the Confederate States to invest in manufacturing, financing, insuring, and shipping cotton rather than relying on the northern states and Great Britain for these services. He died in New Jersey in 1867.