The major river that runs through the Interior Plains is the Mississippi River.

The Mississippi River is one of the longest rivers in North America, flowing from northern Minnesota to the Gulf of Mexico. It serves as a significant geographical feature within the Interior Plains, providing vital waterways for transportation, agriculture, and commerce. The river and its tributaries create a rich ecosystem and have played a crucial role in the history and economy of the regions it traverses, including supporting agriculture in the fertile floodplain areas of the Interior Plains.