 The first change in alignment in MD 268 occurred around 1934 when a bridge was constructed over the B & O Railroad in Perryville, leaving behind Aiken Avenue Extended and Clayton Street. US 222 was extended south to US 40 in Perryville, then on Broad Street, in 1938, assuming all of MD 268. US 222 was reconstructed from US 40 to Port Deposit during World War II to improve access to the naval training center. In 1963, a new alignment was created for the interchange with I-95, bypassing Blythedale Road, which became MD 824. US 222's southern terminus was rolled back to US 1 in Conowingo in 1995; MD 222 was designated along its present course at the same time. MD 222 became the only signed state-numbered highway in Maryland with a number that matches a U.S. Highway.
