Small farms, logging and mining were the principal industries of the settlers in the Blue Ridge Mountains for over a century. Most of the settlers in this early westward movement regarded the Mountains as a an area to get through to more desirable land. The few that settled in the Blue Ridge Region tended to be mostly poor Scotch and Irish immigrants, who formed close knit, clannish communities that did not welcome newcomers and developed a distinct mountain culture.

As American settlers moved into the area, the local Indians were gradually displaced. Despite the accommodations made by the Cherokee, the settlers were insistent upon the Indians being moved west of the Mississippi River. When gold was discovered on Indian lands, the Federal Government ordered the Indians to be moved. Only a few Cherokee that chose to hide in the Blue Ridge Mountains remained behind, with 14,000 Indians being escorted to Oklahoma in 1838. This journey was known as "the Trail of Tears," with only 10,000 survivors of the trip.

Few of the residents of the Blue Ridge Mountains were wealthy enough to own slaves, but men from the region fought on both sides of the Civil war and most tried to remain neutral. These attempts to remain neutral rarely succeeded and raids and harassment were frequent, with several major battles occurring as well. One such notable battle was at the gap at Harpers Ferry, West Virginia, which was was an important railroad traverse.  The end of the Civil War left most of the Blue Ridge Mountain inhabitants even more untrusting and less welcoming than before.

The years following the Civil War and the early 1900's brought an increase in the logging and mining industries in the area. Gradually, the destruction of the forests brought about a backlash against these industries and the Federal and State governments began to establish protected forests and regulate the methods used to harvest the natural resources. The Great Smoky Mountains National Park is the Largest National Park in the U.S., dedicated by the Park Service in 1934. State and National Forests were also widely established throughout the Blue Ridge Mountains over the years.