The river is approximately 325 miles (523 km) long, running through the U.S. states of New York and Pennsylvania. It drains a rural dissected plateau of 11,580 square miles (30,000 km) in the northern Allegheny Plateau, providing the northeastern most drainage in the watershed of the Mississippi River. Its tributaries reach to within 8 miles (13 km) of Lake Erie in southwestern New York.
The Youghiogheny rises in northern West Virginia, in Preston County southeast of the town of Kingwood and near Backbone Mountain. The headwaters are approximately 10 mi (16 km) north of the headwaters of the North Branch of the Potomac River. It flows NNE into Garrett County, Maryland, flowing north past Oakland and roughly parallel to the West Virginia border, separated by approximately 3 mi (5 km). This river enters southwestern Pennsylvania on the border between Fayette and Somerset counties. It flows northwest through a gap in Chestnut Ridge and then past Connellsville. It joins the Monongahela River from the southeast at McKeesport, southeast of Pittsburgh.