The route was initially designated as U.S. Route 213 (US 213) in 1926 when the U.S. Highway System was established, running from Ocean City west and north to US 40 in Elkton. The highway was rerouted to cross the Nanticoke River in Vienna by 1933, with the former route between Mardela Springs and Eldorado becoming a part of MD 313 and the alignment between Eldorado and Rhodesdale becoming part of MD 14. US 213 was rerouted to use the Emerson C. Harrington Bridge over the Choptank River in Cambridge in 1939; the former alignment between Vienna and Easton became MD 331. Meanwhile, the road between Elkton and the Pennsylvania border became Maryland Route 280 (MD 280). US 213 was moved to a bypass of Easton and straight alignment between Easton and Wye Mills in 1948. A year later, the southern terminus was cut back to US 50 in Wye Mills, with an extended US 50 replacing US 213 between Wye Mills and Ocean City. In 1971, US 213 and MD 280 were decommissioned and replaced with MD 213.
