It flows northwest for a few tenths of a mile before turning west-southwest, crossing Pennsylvania Route 61, and entering Mount Carmel Township.

At this point, the creek turns west-southwest for more than a mile, entering a valley and passing into Coal Township.

Soon after entering this township, it turns in a northwesterly direction, flowing alongside Pennsylvania Route 901 and leaving the valley.

At this point, the creek receives the tributary Quaker Run from the right and turns west-southwest along the border of the census-designated place of Marshalton.

Several tenths of a mile after entering Shamokin, the creek receives the tributary Coal Run from the right and turns west-southwest.

[1] Upon entering Coal Township, Shamokin Creek crosses Pennsylvania Route 61 and continues flowing north, passing through a water gap in Big Mountain.

Here, it receives Trout Run from the right and turns west for several tenths of a mile, crossing Pennsylvania Route 61.

The creek then turns southwest for several tenths of a mile and continues flowing along the border until it reaches its confluence with the Susquehanna River.

[3] The entire length of Shamokin Creek is designated as impaired due to high levels of metals from abandoned mine drainage.

In addition to abandoned mine drainage, the creek is impacted by sewage, disruption of the area's natural hydrology, and probably nutrient pollution, sediment, and low levels of dissolved oxygen.

[5] The concentrations of manganese and iron in the upper reaches of Shamokin Creek are 2.72 and 9.74 milligrams per liter (0.00272 and 0.00973 oz/cu ft), while the daily loads are 69.2 and 247.8 pounds (31.4 and 112.4 kg).

[4] In August 1999 and March 2000, the sulfate concentration in the upper reaches of Shamokin Creek ranged from 45 to 220 milligrams per liter (0.045 to 0.220 oz/cu ft), depending on the site.

[5] In August 1999 and March 2000, the nitrogen concentration in the upper reaches of Shamokin Creek ranged from 0.95 to 1.2 milligrams per liter (0.00095 to 0.00120 oz/cu ft), depending on the site.

[8] During this time period, the culm deposits were so extensive that it was one of the few creeks where it was commercially viable to recover coal from its streambed.

[9] The watershed of Shamokin Creek is in the Appalachian Mountains section of the Ridge and Valley physiographic province.

[5] In the early 1900s, vast culm deposits along the creek's banks caused it to lack a defined channel until Snydertown.

[6] The channel of Shamokin Creek is sinuous and flows through rock formations consisting of sandstone, shale, and extensive anthracite deposits.

[10] The upper 51.5 square miles (133 km2) of the watershed, upstream of Big Mountain, are in the Western Middle Anthracite Field, in the Coal Region.

[10] In the early 1900s, the average rate of precipitation in the watershed of Shamokin Creek was 35 to 50 inches (89 to 127 cm) per year.

[12] Historically, it carried waste such as untreated sewage from both the community of Mount Carmel and the area's mining industry.

[13] Most of the land along the upper reaches of Shamokin Creek is commercial and industrial, with trash lining the streambanks.

Further downstream, the creek flows through a broad floodplain, but remains impacted by development and has culm lining its cobble bars.

Downstream of Snydertown, the landscape through which the creek flows is no longer impacted by development or mining and consists of forests and agricultural land.

The Shamokin Creek Restoration Alliance was founded in 1996 with the purpose of "[encouraging] partnerships and develop[ing] incentives and methods to facilitate funding for reclamation of abandoned mine lands (AML) in Shamokin Creek watershed.

In 2002, the Northumberland County Planning Commission received a $75,000 Growing Greener grant to eliminate sources of impairment in the watershed of Shamokin Creek.

In 2003, the Northumberland County Conservation District and the Shamokin Creek Restoration Alliance received more than $500,000 in grants from the United States Environmental Protection Agency to repair abandoned mine drainage sources in the watershed.

[20] The main stem of Shamokin Creek is not inhabited by any aquatic life upstream of the tributary Carbon Run.

[17] Many areas in the upper reaches of Shamokin Creek support little or no macroinvertebrate life due to metals coating the streambed.

[5] A total of 21.6 miles (34.8 km) of Shamokin Creek are navigable by canoe during snowmelt or within two days of hard rain.

[10] Pennsylvania State Game Lands Number 165 is on Little Mountain and is partially in the Shamokin Creek watershed.