The first European Americans in this area were primarily hunters and fur trappers. They settled around the French trading post of French Lick, established in 1710, and later known as Nashville, Tennessee. The settlement's population grew and with them came a transition to growing crops and raising livestock. It soon became apparent that the climate and soil were ideal for tobacco, which quickly became the main cash crop. In 1793, iron ore was discovered between the Cumberland and Tennessee Rivers and more than 20 furnaces were producing iron on the eve of the Civil War. Transportation routes however, were limited around the Fort Campbell region. This greatly restricted the distance these goods could be traded.

Developments in river transportation allowed area settlers to move toward a market-oriented economy. Additionally, a stagecoach route to Nashville ran through Hopkinsville and Clarksville starting in 1819. Turnpikes from Hopkinsville to Russellville and Clarksville were established in 1830 and 1838; further promoting trade between different cities.

The increasing prosperity of the region we interrupted by the outbreak of the Civil War. Sympathies generally sided with the Confederacy. With the fall of nearby Forts Henry, Donelson and Defiance in 1862, the area was quickly occupied by Union forces and remained so for the duration of the war. The local economy was effectively shut down by the closure of the ironworks and confiscation of agricultural produce by military troops. Local men were conscripted into the Union Army, depriving the area of its workforce.

Recovery after the Civil War was slow and the area never again reached its formal level of prosperity in the 19th century. The reorganization of agriculture in the region after the Civil War was gradual and the settlement pattern consisted of a mix of rural freedmen, tenants, and small farm owners. The size of farms tended to be small; about a third of the size of the pre-Civil War plantations.

During the early 20th century, modernization improved agricultural production as well as transportation routes for moving these goods. Tobacco continued to be the most important cash crop. However, price manipulation by tobacco company trusts led to economic hardship and violence as tobacco growers tried to protect their livelihood. The pressure finally eased with the formation of the Tobacco Board of Trade in 1915.

During the 1920s and early 1930s, this region of Tennessee and Kentucky saw the development of paved roads and national highways. US 41 North and South were the first highways to be constructed in the region. Together with US 68, it became one of two paved roads in 1932. The area was also accessible by rail with the Central Tennessee Railway line in proximity and the closest railhead only about 10 miles north of Clarksville. This improved infrastructure heavily influenced the location for the new military base of Camp Campbell on the eve of WWII.