The Mississippi River drains much of the Appalachian region through its tributaries.

The Mississippi River, the second-longest river in the United States, drains a vast portion of the Appalachian region. Several tributaries, including the Ohio River, the Tennessee River, and the Cumberland River, flow from the Appalachian Mountains and feed into the Mississippi River. These rivers carry water from the mountain ranges and contribute to the river's large watershed, which covers parts of the eastern United States. The river system plays a vital role in transporting water, sediment, and nutrients throughout the region.