Interstate 381 (I-381) is a spur from Interstate 81 that provides access to Bristol, Virginia, United States. It runs for 1.7 miles (2.7 km) from the intersection of Commonwealth Avenue (State Route 381) and Keys Street in Bristol north to Interstate 81 at exit 0. The I-81 interchange, the only one on I-381, is signed as exits 1A (I-81 north) and 1B (I-81 south).

The Interstate 381 freeway originally opened to traffic on November 20, 1961, the same time as the part of Interstate 81 that bypasses Bristol to the north.

In its original configuration, the interchange between Interstates 81 and 381 was a single Y interchange, providing access from southbound I-81 to southbound I-381 (via a left exit) and northbound I-381 to northbound I-81. By 1989, ramps were added to make it a full direction T interchange. In 1996, southbound I-81 was moved next to the northbound side, turning the southbound left exit and entrance into right-side ramps.

The entire route is in Bristol, Washington County.