States traversed: Maryland, West Virginia, and Virginia
US Route 340 runs southwest from Frederick, Maryland, into northern Virginia. In Virginia, it runs parallel to Interstate 81's northeast-southwest alignment, just to that highway's east. The northeastern extent of the route is concurrent with US Route 15, and it ends at Interstate 70 as that freeway flanks around the south side of Frederick, Maryland. Just to the southwest, US Route 340 splits from US Route 15, to cut through the eastern extent of West Virginia's eastern panhandle. It then enters Virginia, running parallel to Interstate 81. At Waynesboro in west-central Virginia, US Route 340 bends westerly to enter its final segment, as it's crossing Interstate 64. The southwestern end is at US Route 11, right alongside Interstate 81, at Greenville, Virginia.