It drains an area on the west side of the Allegheny Mountains northward into Pennsylvania, providing a small watershed in extreme western Maryland into the tributaries of the Mississippi River.

[7] According to the Geographic Names Information System, it has also been known historically as:[1] The Youghiogheny rises in northern West Virginia, in Preston County southeast of Aurora and near Backbone Mountain.

[8] In the colonial era and in the early United States, the valley of the river provided an important route of access through the mountains for settlers and military forces from Virginia to western Pennsylvania and the Ohio Country.

In 1754, as a militia officer of the British Colony of Virginia, George Washington followed the river in an attempt to find a water route to Fort Duquesne, then held by the French.

During the uncommonly severe winter of 1787-88, American pioneers to the Northwest Territory departed New England and cut trails westward through the mountains.

Part of the Great Allegheny Passage, a multi-use trail along the former Western Maryland Railway right-of-way, extends from Pittsburgh to Confluence.