[8] The river has been used for transportation across the Allegheny Mountains, between the cities of Baltimore and Washington, D.C., in the east and Pittsburgh in the west.

Although the Western Maryland was abandoned in the 1980s, the right-of-way has been converted into the Great Allegheny Passage, a rail trail bicycle and hiking path.

The two branches flow northward, combining just southwest of Grantsville, Maryland.

The river then continues north into Pennsylvania, following a great arc across the Laurel Highlands of Somerset County to the community of Confluence, where Laurel Hill Creek joins a few meters above the Youghiogheny River.

The Casselman River then forms a natural boundary between Black and Addison Townships on the southeast and Milford, Upper Turkeyfoot, and Lower Turkeyfoot Townships on the northwest, flowing past Casselman, Markleton, and Fort Hill along its way to Confluence.