The Appalachian Mountains are a key part of the Mississippi River Basin.

The watershed encompasses a vast area that collects water from the Appalachian region and channels it into the Mississippi River, which flows southward into the Gulf of Mexico. The mountains play a significant role in the hydrology of the basin, influencing water flow, drainage patterns, and the overall ecosystem of the region. Various rivers and streams originating in the Appalachians, such as the Ohio River and the Tennessee River, are major tributaries of the Mississippi River, further connecting the mountain range to this extensive watershed.