The road heads through a mix of farmland and woodland with some homes, running to the northeast of Ruff Creek and passing through Lippincott.

The route winds through more rural areas, crossing into Washington Township and coming to a partial interchange with I-79, with ramps to and from the northbound lanes of I-79.

A short distance later, PA 221 comes to an intersection with US 19 in Ruff Creek, which connects to ramps providing access to and from the southbound lanes of I-79.

[1][2] PA 221 enters Morris Township in Washington County and becomes Conger Road, heading into wooded areas with a few fields.

PA 221 turns north-northwest and crosses into Blaine Township, heading into residential areas as Constitution Boulevard and curving west into Taylorstown.