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. Alternatively known as Old Baltimore Pike, this road was part of the
Washington–Rochambeau Revolutionary Route used by the French army in September 1781 during their march from
Newport, Rhode Island, to
Yorktown, Virginia, during the
Revolutionary War. In 1817, the Elk and Christiana Turnpike was completed along the path of the Old Post Road; the
turnpike operated until 1838, when Old Baltimore Pike reverted to a public road. 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. The first segment of the modern MD 281 was constructed as a macadam road east from US 40 (now MD 7) on Main Street to Big Elk Creek between 1930 and 1933. In 1948, the
Maryland State Roads Commission, which at the time maintained the major county highways in Cecil County, reconstructed much of Red Hill Road as a gravel road in 1948 before it was to be given a hard surface. The of highway from the west end of the Big Elk Creek bridge along Red Hill Road to the state line was transferred from county to state maintenance through a May 8, 1958, road transfer agreement. MD 281 was reconstructed from Big Elk Creek to the state line in 1960 and 1961; this work included a new four-span, steel beam bridge across Big Elk Creek. The highway was resurfaced with bituminous concrete from MD 7 to Big Elk Creek in 1968 and from the creek to Delaware in 1973. In 2017, construction took place on a $3.1 million project to build a roundabout at Muddy Lane/Kemp Lane; this roundabout opened to traffic in October of that year. ==Junction list==