The route, which is a two-lane undivided highway most of its length, passes through mainly rural areas as well as the towns of Centreville, Chestertown, Galena, Cecilton, Chesapeake City, and Elkton.

In addition, the route is also considered part of the Atlantic to Appalachians Scenic Byway between Chesapeake City and MD 273 in Fair Hill.

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.

The route continues into a mix of woods and farmland before intersecting the northern terminus of MD 309 (Starr Road).

A short distance later, the route reaches a partial cloverleaf interchange with US 301 (Blue Star Memorial Highway).

[1][4] This pairing continues past residences before heading into the downtown area, where the road intersects MD 304 (Water Street).

The one-way pair ends and the route continues north on two-lane undivided Liberty Street, passing by residences and some businesses.

[4] The route heads back into farmland and has a junction with the western terminus of MD 19 (North Main Street), leaving the Church Hill area.

From here, the route turns northwest through more farmland before it passes some residences and businesses near the intersection with the western terminus of MD 544 (McGinnes Road).

[1][4] Past the MD 544 intersection, the road continues through rural areas, but residences and businesses start to increase.

[4] Upon crossing the Chester River, MD 213 enters the town of Chestertown in Kent County, where the route heads northwest on Maple Avenue through residential areas.

Past this intersection, MD 213 continues through residential and commercial areas before it narrows back to a two-lane road.

In Kennedyville, the road crosses the Chestertown Branch of the Northern Line of the Maryland and Delaware Railroad at-grade.

[4] Main Street passes residences before leaving Galena, where the road becomes Augustine Herman Highway again.

The road continues through a mix of farms and woods before reaching the community of Georgetown, where the route passes some homes before crossing the Sassafras River on a drawbridge near a marina.

[1][4] MD 213 enters Cecil County upon crossing the Sassafras River, where it continues north through wooded and agricultural areas with some residences.

After crossing the canal, the road intersects MD 285 (Lock Street), which provides access to the northern portion of Chesapeake City.

[1] Past this intersection, the route heads northwest on Bridge Street, passing through commercial areas as a three-lane road with a center left-turn lane.

[1][4] Past Main Street, the road heads north and passes over Amtrak's Northeast Corridor railroad line before intersecting MD 545 (Elkton Boulevard).

MD 213 enters a mix of woods and farms and passes over Interstate 95 (John F. Kennedy Memorial Highway) without an interchange and CSX's Philadelphia Subdivision railroad line within a short distance of each other.

[1][3][4] From here, the name of MD 213 changes to Lewisville Road and it curves northwest and north through a mix of rural areas and residences before ending at the Pennsylvania border.

From Easton, the route continued north to Wye Mills and followed the present alignment of MD 213 to Elkton.

[18][19] In 1939, the road between US 40 and the northern terminus of US 213 in Elkton and the Pennsylvania border north of Fair Hill was designated MD 280.

[16] On July 28, 1942, the vertical lift bridge carrying US 213 over the Chesapeake & Delaware Canal, built in 1927, was destroyed when the tanker Franz Klasen struck it.