Heading west, the route runs across country to Dickerson, MD, where it descends to parallel the Potomac River through Point of Rocks and Brunswick. It crosses to the south bank of the Potomac just before the Harper's Ferry station stop, then cuts across country to Martinsburg, returning to the Potomac south of Hancock, MD. The line follows the Potomac all the way to Cumberland, thence follows Wills Creek through "The Narrows" and up toward the summit of the line at Sand Patch, PA.

Descending from Sand Patch, the line follows the Youghiogheny River ("Yuck-a-gany") to its junction with the Monongahela River, which it follows for a few miles entering Pittsburgh.