The highway heads north as a two-lane undivided road to the Charles–Prince George's county line at Swanson Creek.

MD 381 continues through the village of Aquasco, which contains the historic homes Sunnyside and Villa DeSales and St. Mary's Rectory.

The highway gradually curves northwest and meets MD 382 (Croom Road) at Poplar Hill.

West of the latter railroad, the highway passes the historic William W. Early House.

MD 381 veers northwest just before reaching its northern terminus at US 301 (Robert Crain Highway) adjacent to Gwynn Park High School and northeast of US 301's partial interchange with MD 5 (Branch Avenue).

[6][7] MD 381 was completed as a gravel road from Aquasco to its southern terminus at Patuxent in 1933.