The state highway runs 5.38 miles (8.66 km) from MD 155 in Hopewell Village north to U.S. Route 1 (US 1) in Darlington.

The state highway heads north as two-lane undivided Darlington Road through farmland.

After passing through the Silver Houses Historic District, the state highway crosses Deer Creek.

At Trappe Church Road, MD 161's name changes to Main Street and the highway passes through the village of Darlington, which is contained within its own historic district.

At the north end of the village, the state highway meets the southern end of MD 623 (Castleton Road) and passes northeast of the Deer Creek Friends Meetinghouse before reaching its northern terminus at US 1 (Conowingo Road).