The Casselman River rises in Garrett County atop the plateau of western Maryland as two branches, the south one east of Meadow Mountain, the north one farther west, between Meadow Mountain and Negro Mountain. 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, Pennsylvania to the community of Confluence, where Laurel Hill Creek joins a few meters above the Youghiogheny River.
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. Two railroads followed the Casselman River from Meyersdale, Pennsylvania to Confluence. First is the B&O Railroad, running between Baltimore and Pittsburgh, which was completed in 1827, and is currently owned by CSX. Second is the Western Maryland Railway, which ran from Cumberland, Maryland to Connellsville, Pennsylvania. 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.