MD 281 and its continuation in Delaware were originally blazed in the 18th century as part of the Old Post Road between Baltimore and Philadelphia.

The highway designation was extended east to the state line in the late 1950s; that extension was reconstructed in the early 1960s.

MD 281 heads east as two-lane undivided Main Street and leaves the town by crossing Big Elk Creek.

[1][2] What is now MD 281 and its continuation in Delaware was the Old Post Road used to connect Christiana Bridge with the head of the Elk River, and by extension Philadelphia and Baltimore, in the 18th century.

[3] By the 1920s, the Old Baltimore Pike was supplanted by a parallel highway to the south from Elkton to Wilmington that was chosen as the route of US 40.