Among the locations known as The Great Valley is one in the eastern United States of America, lying behind the first ridge of mountains (the Blue Ridge) extending from New York to Georgia.

The eastern American Great Valley is a geologic region characterized by easily eroded shale or limestone strata and not associated with a single river, as the word valley implies. Portions of its length are indeed river valleys, such as the Shenandoah Valley and the Cumberland Valley are within the eastern American Great Valley region. The Great Valley was a main route for settlement and commerce in the United States along the Great Wagon Road from Philadelphia, Pennsylvania. The Wilderness Road into Kentucky and Tennessee branched from the Great Wagon Road at what is now known as Roanoke, Virginia. Today, the main thoroughfare within most of the Great Valley is Interstate 81.