Buttermilk Creek begins in Fords Lake in Newton Township, Lackawanna County.

It then enters Falls Township, Wyoming County, where it eventually turns northwest for a few tenths of a mile, crossing Pennsylvania Route 307.

The creek then gradually turns west and then southwest for more than a mile, remaining in its valley and flowing alongside Pennsylvania Route 307.

After a few tenths of a mile, it turns west and receives the tributary Falls Creek from the left.

After a few tenths of a mile, it passes Buttermilk Falls and reaches its confluence with the Susquehanna River.

[4] In the early 1900s, the average annual rate of precipitation in the watershed of Buttermilk Creek was 35 to 40 inches (89 to 102 cm).

[1] The topography of the watershed of Buttermilk Creek was described as "rough and hilly" in the Water Resources Inventory Report in 1921.

[5] In the distant past, accumulating piles of glacial drift caused Buttermilk Creek to alter its course and flow over a series of cliffs as a waterfall.

Additionally, there are a few patches of alluvial fan, peat bogs and other wetlands, lakes, and sandstone and shale pits in the watershed.

[8] In the early 1900s, the main industries in the watershed of Buttermilk Creek included agriculture and a summer resort.

Major settlements in the watershed at this time included Mill City, Falls, and Lake Winola.

[5] A steel stringer/multi-beam or girder bridge carrying T362/Creek Flats Road over Buttermilk Creek was built in 1916 in Falls and was repaired in 1982.

A concrete slab bridge carrying State Route 2027 over the creek was built in 1958 in Falls Township, Wyoming County and is 24.0 feet (7.3 m) long.

A wood stringer/multi-beam or girder bridge carrying T373 over the creek was built in 1978 in Falls Township, Wyoming County and is 32.2 feet (9.8 m) long.

A prestressed box beam or girders bridge carrying State Route 2015 was constructed across the creek in 1990 in Falls Township, Wyoming County and is 60.0 feet (18.3 m) long.