The Ohio was a primary route for early settlers of the frontier, who floated flatboats down the river into the wilderness along the southern edge of the Northwest Territory. Later it became a shipping corridor for barges loaded with coal from the mines of westeyn Pennsylvania and West Virginia. Major Population centers along the Ohio are Pittsburgh, Wheeling, Portsmouth and Maysville Ohio, the Cincinnati/Northern Kentucky area, Louisville, and Cairo, Illinois.

Due to the 23 dams along its length, the Ohio River is actually better described as a series of lakes which occasionally spill into each other.