The road is paralleled by Interstate 95 (I-95, Delaware Turnpike) to the north and U.S. Route 40 (US 40, Pulaski Highway) to the south.

Old Baltimore Pike begins at the Delaware–Maryland state line near the city of Newark, Delaware, where the highway continues west into Maryland as MD 281.

Here, the roadway heads across the Christina River and passes Cooch's Bridge, a historic battle site of the American Revolutionary War.

It then crosses Norfolk Southern's Delmarva Secondary railroad line at-grade and meets DE 72 at a junction.

[2][3] After this junction, Old Baltimore Pike continues past suburban neighborhoods, gaining a center left-turn lane and intersecting Salem Church Road.

[2][3] The entire length of Old Baltimore Pike is part of the Washington–Rochambeau Revolutionary Route, a National Historic Trail.