[2] Knoxville is situated at the base of South Mountain directly beside the Potomac River to the immediate east of the water gap leading towards Harpers Ferry, West Virginia.

By the early 19th century, a village began to form along the main road leading from Frederick, to Harpers Ferry, then the site of one of the two national armories in the United States.

[4] Many of the vernacular and Greek Revival-styled buildings seen in the village today date from the 1840s and 1850s when the railroad, canal, and industry along the Potomac River contributed to Knoxville's growth.

[5] Despite the interruption of the Civil War, Knoxville continued to thrive as a local transportation hub throughout the third quarter of the 19th century.

[5] In 1890, the Baltimore and Ohio Railroad began construction of a massive rail yard in the village of Berlin, 2 miles (3 km) to the east.