Agricultural impacts have caused most of the streams in the watershed of the creek (including the main stem) to be impaired.

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.

It then turns south-southeast for about a mile, flowing close to the county line and crossing Pennsylvania Route 642.

It then turns south for a few tenths of a mile, passing the Rishel Covered Bridge as it continues flowing along the border.

[1] Chillisquaque Creek joins the West Branch Susquehanna River 5.01 miles (8.06 km) upriver of its mouth.

[4] However, in the 1980s, the concentrations of pollutants in the creek were relatively low, despite being increased by discharges from a nearby power plant.

For instance, the selenium concentration was consistently under 0.010 milligrams per liter, the United States Environmental Protection Agency criterion for that pollutant.

[5] Between 1980 and 2014, the highest average annual discharge of Chillisquaque Creek at Washingtonville was 146.0 cubic feet per second (4.13 m3/s), in 2011.

[13] The creek's drainage basin mainly consists of rolling agricultural land, with some forested floodplains.

[14] In places, it has high, muddy banks, and is generally "placid", save for some riffles and gravel bars.

[8][15] Chillisquaque Creek cuts a broad and almost flat valley through rock of the Hamilton Group.

However, A. Joseph Armstrong (author of Trout Unlimited's Guide to Pennsylvania Limestone Streams) was unable to find the springs.

The channel of the creek is sinuous and flows through rock formations consisting of sandstone and shale.

Rock of the Hamilton Group is common in the area as well and is in places covered with sandstone boulders of the Pocono Formation.

[14] In the early 1900s, the average annual rate of precipitation in the watershed of Chillisquaque Creek was 35 to 45 inches (89 to 114 cm).

[11] However, other possible meanings of the word include "flight of the wild goose", "frozen duck", and "man made perfect".

The first Methodist camp meeting in the area was held on the creek 1.5 miles (2.4 km) from the West Branch Susquehanna River in August 1806.

[23] In the early 1900s, the main industries in the creek's watershed included agriculture and clay mines.

Major communities included Exchange, Jerseytown, Potts Grove, Washingtonville, Strawberry Ridge, and White Hall.

[31][32] In 1986, it contained many of the species found in the West Branch Susquehanna River, including rock bass.

[33] A tract of forested floodplain known as the Chillisquaque Creek Natural Area (or Bucknell Preserve, Tobias Marsh, or Mexico Road Swamp) is located in Liberty Township, Montour County.

[15] Reaches of Chillisquaque Creek in Derry Township, Montour County would benefit from additional riparian buffering consisting of native trees to mitigate the effects of nonpoint source pollution.

[8] Virginia cowslips, mint, skunk cabbage, mountain honeysuckle, and scallions also are common along it towards the end of April.

Additionally, several mussel species that require high levels of water quality to survive have been observed in the creek.

[15] In the Montour County reach of the watershed of Chillisquaque Creek, livestock is commonly allowed access to streams.

[4] At least 17.9 miles (28.8 km) of Chillisquaque Creek, from Pennsylvania Route 54 at Washingtonville downstream to its mouth, are navigable by canoe.

The difficulty rating of the creek is 1 and the scenery is described in Edward Gertler's book Keystone Canoeing as "good".

The creek is suitable for beginners and is typically canoeable from March to May, with the exception of dry years.

[8] A greenway corridor for Chillisquaque Creek was proposed in the Montour County Comprehensive Plan.

[36] A reach of Chillisquaque Creek was once a third-priority candidate for a Pennsylvania Scenic Rivers designation.