The Appalachian Region consists of highlands running from the mountains of west central New York in the north to central Alabama in the south. It includes the Appalachian Mountains and a number of surrounding features.

The mountains lie roughly parallel to the Atlantic Coast and rise from the Coastal Plain, a flat, low-lying area that stretches along the East Coast from southern Maine to Texas. Between the coastal plain and the mountains is the Piedmont, an area of rolling foothills.

To the west of the Appalachians is the Appalachian Plateau, an area of hilly uplands that extends from Pennsylvania to Alabama and descends to the lowlands of the central U.S.

The museum contains 30 historical log buildings on 63 acres. Included is an old 1800 schoolhouse, jail cells from 1874, home of Mark Twain's parents built in 1790 and an old whiskey still.