The Okolona Historic District is locally significant for what it represents about the historical development of Okolona as a center of commerce for Chickasaw County, and for its architecture, as a locally significant collection of 19th and early 20th century buildings, particularly notable for the variety of its historic churches and public buildings.

The period of significance spans a century, from circa 1850, when the earliest surviving buildings were constructed, to 1950, which marked the beginnings of economic changes in the area in the aftermath of the Second World War. The buildings in the district illustrate the commercial and residential development of Okolona as a center for the transportation of cotton to market, as a commercial center serving the local rural area, and as a center of government as the seat of the Eastern District of Chickasaw County. (The other county seat is located in Houston.)