The highway runs 11.36 miles (18.28 km) from MD 7 in Perryville north to U.S. Route 1 (US 1) near Conowingo.

MD 222 connects Perryville, Port Deposit, and Conowingo along its route paralleling the Susquehanna River in western Cecil County.

MD 222 continues northeast past US 40 as Perryville Road, which crosses over CSX's Philadelphia Subdivision railroad line.

At the north end of the interchange, the highway briefly re-enters the town of Perryville and intersects the ramps to and from southbound I-95 and Chesapeake Overlook Parkway, which serves as the entrance road to Hollywood Casino Perryville and the Great Wolf Lodge resort to the west.

[1][2] MD 222 heads west through farmland, crossing Happy Valley Branch before passing the entrance to the former United States Naval Training Center Bainbridge, which contains the Edward W. Haviland House and the original campus of the Tome School.

The highway descends from a high bluff to the Susquehanna River, during which southbound MD 222 has a climbing lane.

Upon entering the town limits of Port Deposit, MD 222's name changes to Main Street and the highway makes a sharp turn to the north to parallel the river and Norfolk Southern Railway's Port Road Branch, both of which are located southwest of the road.

[8] The American Association of State Highway and Transportation Officials (AASHTO) approved rolling back the southern end of the US 222 designation from US 40 to US 1 at their April 1995 spring meeting.

[9] The Maryland State Highway Administration proposed and AASHTO approved the redesignation of US 222 to MD 222 from US 40 to US 1 in February 1996; however, the new designation had already been enacted officially and marked publicly in 1995.

[22][27] The I-95 interchange was converted from a standard diamond to a four-ramp partial cloverleaf with all four ramps east of MD 222 between 1993 and 1994.

The truck route then headed west on US 1 (in a wrong-way concurrency) to US 222's southern terminus in Conowingo.

MD 222 has three auxiliary routes that are maintained by the Maryland Transportation Authority (MDTA) and provide access to the authority's facilities around I-95's interchange with MD 222 and the John F. Kennedy Memorial Highway toll plaza to the east of the Millard E. Tydings Memorial Bridge.