The Interstate 381 constitutes a freeway spur from I-81 toward Downtown Bristol, Virginia. There are no mainline interchanges along the highway. Unsigned Virginia State Route 381 extends south from the freeway end at Keys Street to U.S. 11/19/421 at Euclid Avenue.
Interstate 381 opened to traffic by 1962.1
Signs for Virginia 381 along Commonwealth Avenue were removed by 2005. The set of flashers with Keys Street at the freeway south end were replaced with traffic lights light by 2007. Widening of Interstate 81 at the north end was completed by 1998.