The Buffalo River is one of the few remaining unpolluted, free-flowing rivers in the lower 48 states offering both swift-running and placid stretches. The Buffalo National River encompasses 135 miles of the 150-mile long river. It begins as a trickle in the Boston Mountains 15 miles above the park boundary. Following what is likely an ancient riverbed, the Buffalo cuts its way through massive limestone bluffs traveling eastward through the Ozarks and into the White River. The national river has three designated wilderness areas within its boundaries.

The Buffalo National River encompasses the diversity of the natural resources that are the Ozarks. This was acknowledged by an U.S. House of Representatives Committee Reports (1972) that explained the basis for the establishment of the Buffalo National River. It stated, "Because it is a pure, free-flowing stream which has not been significantly altered by industry or man, it is considered to be one of the country’s last significant natural rivers. It is not one single quality, but the combination of its size, its completeness, its wild qualities, and its associated natural, scenic and historic resources that makes the Buffalo worthy of national recognition."

Many prehistoric and historic cultural sites are located in the park, some dating back more than 10,000 years. These sites range from terrace village sites, to bluff shelters once occupied by Archaic Indians, to cabins built by early settlers. In Boxley valley, Ozark farmers still live in harmony with the land. Other areas, such as the Parker-Hickman Farmstead in Erbie, the Rush Mining District (Arkansas' only ghost town), the 1930s Collier Homestead at Tyler Bend, and the Civilian Conservation Corps structures at Buffalo Point, represent the progression of Buffalo River history. Trails in these areas lead the hiker back in time to an era when the natural and cultural world were one.