Several small communities are located in the watershed, which include Beaver Meadows, Buck Run, Glen Dower, Minersville, Pottsville, Cressona, and Schuylkill Haven.

Mild amounts of acid mine drainage affect the West Branch and its tributaries.

From its headwaters near Interstate 81, the river flows southeast through several water gaps in the Ridge-and-Valley Appalachians, ending at its confluence with the Schuylkill River in Schuylkill Haven.

It then flows south and southeast past Minersville, and finally east through a narrow canyon, where it receives Indian Run on the right bank.

After exiting the canyon, it turns south and enters an increasingly wide valley.