The area around the Big Spring was inhabited by prehistoric Native Americans as early as 10,000 years ago. The first settlement was a French trading post and Indian village about 1780 on Cold Water Creek (Spring Creek) near the river. The first permanent white settlers were Michael Dickson and family, who arrived by keel boat about 1817, followed shortly by four brothers-in-law, Isaiah McDill, James McMann, Hugh Finley and David Matthews. Jackson's Military Road was constructed through Tuscumbia 1817. The town was incorporated on December 20, 1820 as Ococoposa (Oka Kapassa), a Chickasaw expression meaning Cold Water, with Thomas Limerick as the first mayor. General John Coffee laid out the town and a land sale was held in 1820. The name of the town was changed to Big Spring in 1821 and changed again to Tuscumbia in 1822 in honor of the Chickasaw chief who lived here when the early settlers arrived.
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During the antebellum period, Tuscumbia thrived with commerce aided by its agrarian base and the incorporation of the Tuscumbia Railroad Company, the first railroad west of the Appalachian Mountains. The railroad connected the town with its steamboat landing on the Tennessee River. Later, it was extended through Courtland to Decatur. Several large bands of Cherokee and Creeks passed through Tuscumbia on the "Trail of Tears" during the Indian Removal in the late 1830s. During the Civil War, the town was occupied several times by Union troops with sharp skirmishes being fought. In 1867, Colbert County was formed from the northern half of Franklin County and was named for prominent Chickasaw leaders George and Levi Colbert. Tuscumbia became the county seat. Helen Keller, the internationally known blind and deaf humanitarian, was born here in 1880 at Ivy Green.
Tuscumbia is one of Alabama's oldest towns with more than 100 antebellum commercial buildings, churches and homes. Tuscumbia Historic District is listed on the National Register of Historic Places.