Dothan was founded on the site of Poplar Head Springs, which was an important crossroads in the Muscogee lands.

The town was incorporated in 1885, and began a period of great expansion with the coming of the Alabama Midland Railway in 1889.

The oldest buildings in the district date from the 1900s, including the three-story Wadlington Hotel (built 1900, demolished 2012) and the Neoclassical First National Bank (1907).

Cotton had replaced lumber as the economic engine of the region, but the boll weevil outbreak of the 1910s sent Dothan into a recession.

The importance of the downtown core declined after the 1960s, as retail establishments relocated to outlying areas.