The Cherokee people once inhabited the land that is now Panther Creek State Park. In the early 18th century, Cherokee Indians and European settlers encountered one another on the lands surrounding Panther Creek. One thing that united these two groups was their common fear of the panther, which was called “Tonawanda” by the Cherokee and “Wachuka” by the Europeans.

The first American survey of the area, conducted in the 1760s, indicated that a “wild cat” was the creature of concern. In the late 18th century the Cherokee ceded most of their land to the federal government, which then opened the area to settlers. The area surrounding Panther Creek State Park was first settled by William and Ellen Mosely, who constructed a log cabin on the banks of the creek in 1816. In the late 1820s William’s son James Moseley constructed a gristmill on the banks of Panther Creek. The family operated the mill until 1840. In 1848 a road was constructed through the park, connecting Morristown, Tennessee with Fort Sanders, located on the opposite side of Cherokee Lake. This road, now Tennessee State Route 342, still runs through the park and continues to be maintained by the Tennessee Department of Transportation.