Chillisquaque Creek begins at the confluence of East Branch Chillisquaque Creek and Middle Branch Chillisquaque Creek near the northern border of Derry Township, Montour County.
It flows west-southwest for a few tenths of a mile before turning south-southwest.
After several tenths of a mile, it turns west for a short distance and receives the tributary West Branch Chillisquaque Creek from the right.
The creek then turns south-southeast for more than a mile, flowing alongside Pennsylvania Route 54 and crossing it once.
In this reach, it briefly flows alongside the western border of Washingtonville before crossing Pennsylvania Route 254 and receiving the tributary Mud Creek from the left.
The creek then begins flowing in a roughly west-southwesterly direction and soon enters Liberty Township.
It continues flowing in a similar direction in Liberty Township (though it does flow north, west, and then south for several tenths of a mile at one point), flowing through a broad valley with Limestone Ridge on the north and receiving many unnamed tributaries from both sides.
After several miles, the creek leaves the valley and crosses Interstate 80.
Several tenths of a mile further downstream, it exits Liberty Township and Montour County.

Upon exiting Montour County, Chillisquaque Creek enters East Chillisquaque Township, Northumberland County.
It then turns south-southeast for about a mile, flowing close to the county line and crossing Pennsylvania Route 642.
In this reach, it receives Beaver Run, its last named tributary, from the left.
The creek then turns southwest for a few tenths of a mile before turning south for a similar distance.
It then turns west for several tenths of a mile before turning southwest.
The creek crosses Pennsylvania Route 45 and meanders in a southwesterly direction for more than a mile, flowing along the border between East Chillisquaque Township and West Chillisquaque Township.
It then turns south for a few tenths of a mile, passing the Rishel Covered Bridge as it continues flowing along the border.
After this, the creek turns west-southwest, entering West Chillisquaque Township, before turning south and then west.
For more than a mile, the creek flows through a valley between Montour Ridge and a smaller hill.
Upon leaving the valley, the creek crosses Pennsylvania Route 147 and Pennsylvania Route 405 and heads in a southwesterly direction for several tenths of a mile before reaching its confluence with the West Branch Susquehanna River.

Chillisquaque Creek joins the West Branch Susquehanna River 5.01 miles (8.06 km) upriver of its mouth.
Chillisquaque Creek begins at the confluence of East Branch Chillisquaque Creek and Middle Branch Chillisquaque Creek near the northern border of Derry Township, Montour County. It flows west-southwest for a few tenths of a mile before turning south-southwest. After several tenths of a mile, it turns west for a short distance and receives the tributary West Branch Chillisquaque Creek from the right. The creek then turns south-southeast for more than a mile, flowing alongside Pennsylvania Route 54 and crossing it once. In this reach, it briefly flows alongside the western border of Washingtonville before crossing Pennsylvania Route 254 and receiving the tributary Mud Creek from the left. The creek then begins flowing in a roughly west-southwesterly direction and soon enters Liberty Township. It continues flowing in a similar direction in Liberty Township (though it does flow north, west, and then south for several tenths of a mile at one point), flowing through a broad valley with Limestone Ridge on the north and receiving many unnamed tributaries from both sides. After several miles, the creek leaves the valley and crosses Interstate 80. Several tenths of a mile further downstream, it exits Liberty Township and Montour County.
Upon exiting Montour County, Chillisquaque Creek enters East Chillisquaque Township, Northumberland County. It then turns south-southeast for about a mile, flowing close to the county line and crossing Pennsylvania Route 642. In this reach, it receives Beaver Run, its last named tributary, from the left. The creek then turns southwest for a few tenths of a mile before turning south for a similar distance. It then turns west for several tenths of a mile before turning southwest. The creek crosses Pennsylvania Route 45 and meanders in a southwesterly direction for more than a mile, flowing along the border between East Chillisquaque Township and West Chillisquaque Township. It then turns south for a few tenths of a mile, passing the Rishel Covered Bridge as it continues flowing along the border. After this, the creek turns west-southwest, entering West Chillisquaque Township, before turning south and then west. For more than a mile, the creek flows through a valley between Montour Ridge and a smaller hill. Upon leaving the valley, the creek crosses Pennsylvania Route 147 and Pennsylvania Route 405 and heads in a southwesterly direction for several tenths of a mile before reaching its confluence with the West Branch Susquehanna River.
Chillisquaque Creek joins the West Branch Susquehanna River 5.01 miles (8.06 km) upriver of its mouth.
Chillisquaque Creek