In the 20th century, the upper reaches of the West Branch turned a yellow/orange color due to sulfurous drainage from nearby and abandoned deep bituminous coal mines.

In the late 18th century, Cherry Tree marked the frontier between the Pennsylvania Colony and the Shawnee and Lenape lands to the west as specified by treaty.

During Pennsylvania's great lumbering era, the most significant log drive was conveyed on the West Branch of the Susquehanna River.

The Susquehanna's West Branch Canal Division further shaped the corridor, linking towns and villages and providing vital opportunities for commerce.

The lands of the West Branch Susquehanna River Valley were then chiefly occupied by the Munsee phratry of the Lenape (or Delaware) people and were under the nominal control of the Five (later Six) Nations of the Iroquois.

Her village at the mouth of Loyalsock Creek on the West Branch Susquehanna River was an important stopping point for the Moravian missionaries who were spreading the gospel throughout the wilderness of Pennsylvania during the 1740s.

Homes and fields were abandoned, with livestock driven along and a few possessions floated on rafts on the river east to Muncy, then further south to Sunbury.

[9] In 1790, Timothy Matlack, Samuel Maclay and John Adlum were commissioned by the Supreme Executive Council of the Commonwealth of Pennsylvania to survey the headwaters of the Susquehanna and explore a route for a passageway to connect the West Branch with the waters of the Allegheny River.

[10] The Fair Play Men were illegal settlers (squatters) who established their own system of self-rule from 1773 to 1785 in the West Branch Susquehanna River Valley of Pennsylvania.

In a remarkable coincidence, the Fair Play Men made their own declaration of independence from Britain on July 4, 1776, beneath the "Tiadaghton Elm" on the banks of Pine Creek.

It was on the east side of Antes Creek, overlooking and on the left bank of the West Branch Susquehanna River on a plateau in Nippenose Township south of modern-day Jersey Shore in western Lycoming County.

[11] Despite being abandoned and attempts by the attacking British forces to burn it down, Fort Antes was one of only two structures in the valley to survive the Big Runaway.

The men working at the end of the boom would sort the logs according to their corresponding brand and float them into the correct holding pond along the bank of the river.