The state highway runs 1.56 miles (2.51 km) from Ape Hole Road at Lawsonia north to Main Street at the city limit of Crisfield in southwestern Somerset County.

MD 380, which is the southernmost state highway in Maryland, provides access to a suburban area south of Crisfield.

MD 380 begins at a three-way intersection with Byrdtown Road, which heads southwest, and Ape Hole Road, which heads southeast toward Ape Hole Creek, an inlet of the Pocomoke Sound.

The state highway heads north as two-lane undivided Lawsonia Road through a residential area.

[1][3] MD 380 was constructed east and south from the pre-existing concrete Main Street in Crisfield starting in 1934.