The trail was also followed by explorers and traders of European origin known as Kaintucks, who traversed the area in small flat-bottom boats. These traders were usually from Kentucky and floated merchandise from the Ohio River and Mississippi Rivers. The trail was also traversed by early settlers who established small family farms. Many of these first farmers became or were replaced by planters who acquired vast landholdings that were worked by enslaved persons who were led down this trail by foot. Slave traders led caravans of enslaved persons from Virginia and other Southern states to the area known as the Old Southwest in the early 1800s.
Meriwether Lewis died along the trail in Tennessee. President Andrew Jackson also traveled the Natchez Trace. The proliferation of steamships led to an end to the trail's use.Today, the former trail is part of the second-largest parkway in the United States.