The “upper elevation” flowing north and east extends roughly from Winona to Leavittsburg and is generally rural in nature, meandering through game lands, forests, and agricultural properties.

The mainstem (lower elevation) flowing mainly southeast extends roughly from Leavittsburg to the river's mouth near New Castle, Pennsylvania.

Portions of this section are more densely populated and heavily industrialized, including the cities of Warren, Niles, Youngstown, Campbell, and others.

The mainstem area has a population of over 500,000 and has a long history of steel making, coke production, and other industries.

But analysts estimate that 750,000 cubic yards (573,416 m³) of river bed and shoreline sediment, over a 30-mile (48.2 km) stretch of the mainstem from Leavittsburg to the Pennsylvania border, is so heavily polluted that it will need to be remediated.

Since 1988, the Ohio Department of Health has maintained an advisory against swimming or wading in the river between Leavittsburg and the Pennsylvania border, and also advises against eating fish caught there.

The Corps of Engineers estimates that the remediation will take up to 15 years to complete and cost in excess of US$100 million.

Cities and towns along its course include: The Mahoning river is susceptible to frequent flooding during high rain events.