Mahoning Creek begins in a valley in Madison Township, Columbia County.
It flows south for a short distance before turning west-southwest for several tenths of a mile, exiting Columbia County.

Upon exiting Columbia County, Mahoning Creek enters West Hemlock Township, Montour County.
It flows south-southwest alongside Pennsylvania Route 642 for a few miles before crossing Pennsylvania Route 642 and entering Derry Township.
The creek then turns south for a few miles and enters Valley Township.
In Valley Township, it continues flowing south in its valley and crosses Pennsylvania Route 642 before continuing south.
The creek eventually enters a much broader valley and flows away from Pennsylvania Route 642.
After several tenths of a mile, it crosses Interstate 80 and receives Kase Run, its first named tributary, from the left.
The creek then meanders west for several tenths of a mile and then turns southwest, flowing alongside Pennsylvania Route 642 again.
Not far from Mausdale, Mahoning Creek crosses Pennsylvania Route 642 and Pennsylvania Route 54 and receives the tributary Mauses Creek from the right.
The creek then turns southeast and begins flowing alongside Pennsylvania Route 54 into Mahoning Township and through a water gap in Montour Ridge.
It enters Danville and leaves behind the water gap, turning south-southwest and crossing US Route 11.
After a few tenths of a mile, the creek receives Sechler Run, its last named tributary, from the left, and turns west-northwest.
After several tenths of a mile, it exits Danville and enters Mahoning Township briefly before turning sharply southeast and reentering Danville.
After a short distance, the creek reaches its confluence with the Susquehanna River.

Mahoning Creek joins the Susquehanna River 136.26 miles (219.29 km) upstream of its mouth.
Mahoning Creek begins in a valley in Madison Township, Columbia County. It flows south for a short distance before turning west-southwest for several tenths of a mile, exiting Columbia County.
Upon exiting Columbia County, Mahoning Creek enters West Hemlock Township, Montour County. It flows south-southwest alongside Pennsylvania Route 642 for a few miles before crossing Pennsylvania Route 642 and entering Derry Township. The creek then turns south for a few miles and enters Valley Township. In Valley Township, it continues flowing south in its valley and crosses Pennsylvania Route 642 before continuing south. The creek eventually enters a much broader valley and flows away from Pennsylvania Route 642. After several tenths of a mile, it crosses Interstate 80 and receives Kase Run, its first named tributary, from the left. The creek then meanders west for several tenths of a mile and then turns southwest, flowing alongside Pennsylvania Route 642 again. Not far from Mausdale, Mahoning Creek crosses Pennsylvania Route 642 and Pennsylvania Route 54 and receives the tributary Mauses Creek from the right. The creek then turns southeast and begins flowing alongside Pennsylvania Route 54 into Mahoning Township and through a water gap in Montour Ridge. It enters Danville and leaves behind the water gap, turning south-southwest and crossing US Route 11. After a few tenths of a mile, the creek receives Sechler Run, its last named tributary, from the left, and turns west-northwest. After several tenths of a mile, it exits Danville and enters Mahoning Township briefly before turning sharply southeast and reentering Danville. After a short distance, the creek reaches its confluence with the Susquehanna River.
Mahoning Creek joins the Susquehanna River 136.26 miles (219.29 km) upstream of its mouth.
Mahoning Creek (Susquehanna River tributary)