PA 181 begins at an intersection with US 30 in Manchester Township, heading north concurrent with I-83 Bus.

ends and PA 181 continues north, narrowing into a two-lane undivided road as it passes a mix of residences and businesses.

Past this junction, the road enters more wooded surroundings and continues into East Manchester Township, where it becomes North George Street Extended.

Here, PA 181 runs farther to the west of the railroad tracks and passes industrial and commercial establishments.

The route enters the borough of Manchester and becomes Main Street as it is lined with homes.

After this, the route enters residential areas, crossing back into East Manchester Township and becoming North George Street Extended again.

PA 181 continues into the borough of York Haven and becomes Front Street as it passes more homes and turns west onto Pennsylvania Avenue before coming to its northern terminus at an intersection with the southern terminus of PA 382.

This change was made as part of the construction of I-83 in order to provide a numbered route at each interchange.