The Ohio River is often considered the eastern boundary of the Mississippi River System.

The Ohio River serves as a vital eastern boundary of the Mississippi River System, marking a key dividing line in the river basin. Flowing from the eastern U.S. and joining the Mississippi River at Cairo, Illinois, the Ohio River contributes significant water volume and supports navigation and trade. Its strategic location has historically made it a crucial route for commerce, connecting the eastern states to the broader Mississippi Basin and fostering economic growth across the region.