Pontotoc is a Chickasaw word that means, “Land of the Hanging Grapes.” A section of the city largely along Main Street and Liberty Street has been designated the Pontotoc Historic District and is listed on the National Register of Historic Places.

[6] The Treaty of Pontotoc Creek, part of U.S. president Andrew Jackson's Indian Removal policy, ceded millions of acres of Native American lands and relocated the Chicakasaw west of the Mississippi River.

The Chickasaw nation occupied this area long before Europeans colonized the Southeast, the last in a succession of indigenous peoples who had this territory for thousands of years.

The Town Square Museum is located in the historic US post office near the county courthouse.

It was one of numerous projects of the Works Progress Administration (WPA) under President Franklin D. Roosevelt.

Investment in this program created work opportunities in construction of needed public buildings and infrastructure across the country, employing thousands of workers.

A mural in the post office lobby, titled The Wedding of Ortez and SaOwana - Christmas 1540 (1939), was commissioned as public art.

It depicts a legendary feast given by Hernando de Soto to celebrate what was said to be the first recorded Christian marriage on the North American continent.

The wedding is said to have taken place in Pontotoc County during a visit by de Soto's party, but there is little documentation of such an event.

[8] The mural was painted in 1939 by artist Joseph Pollet, who had immigrated to the US as a child with his family from Germany.

It celebrates the Maclura pomifera (Osage orange) (also known as bois d'arc, or bowdock) tree located next to the historic mansion, Lochinvar; both survived a massive tornado in 2001.