Maryland Route 381 (Brandywine Road) is a state highway in Charles County and Prince George's County. It begins by branching off of MD 231 (Prince Frederick Road) in eastern Charles County and heads north for 1.38 miles (2.22 km) before crossing into the south-eastern tip of Prince George's County. In Prince George's County, it continues onwards through mostly rural areas and the unincorporated communities of Aquasco and Baden before reaching its northern terminus at US 301 in Brandywine.

The portion of Route 381 from MD 231 up until the intersection with MD 382 (Croom Road) is a component of the Maryland Scenic Byways system as Byway #13, Star-Spangled Banner.

It is a two-lane highway, aligned north–south, and runs for a total length of 15.91 miles (25.60 km).

It begins by branching off of MD 231 (Prince Frederick Road) in eastern Charles County and heads north for 1.38 miles (2.22 km), serving residences along its path, before crossing into the south-eastern tip of Prince George's County over Swanson Creek. In Prince George's County, it immediately passes over a railroad alignment and continues onwards through heavily wooded rural areas, with some farmland lining the route. It passes through the unincorporated community of Aquasco and Baden, where it intersects MD 382 (Croom Road). Many homes and important facilities are served over a long stretch of the route before it returns to woodland, curving to the northwest. As it enters Brandywine, it crosses three sets of railroad tracks and is intersected by several city streets before reaching its northern terminus at US 301.

Beyond the official end of MD 381 and state maintenance, Brandywine Road continues on to an intersection with MD 373 (Accokeek Road) and further on, a signal-controlled intersection with MD 5 (Branch Ave). It then crosses over MD 5 into a series of suburban areas until it terminates in Clinton at Woodyard Road / Piscataway Road (MD 223). This configuration is subject to change in the future depending on the results of a MDSHA project to revamp the MD 5 / MD 373 / Brandywine Road interchange.

MD 381 serves the following points of interest: