The Mississippi River and its vast basin play a critical role in supporting ecological, economic, and social systems in the United States. However, managing this extensive watershed has become increasingly challenging due to a range of complex issues. This paper explores the historical developments in the watershed management of the Mississippi River, including navigation, flood control, sediment management, water supply, and pollution control. The current issues affecting the resilience, sustainability, and equity of the river and its basin are analyzed, leading to the formulation of a vision for its future. To realize this vision, various strategies are proposed, including embracing integrated water resources management, leveraging information technologies, synergizing green, grey, and blue infrastructure measures, and preparing for extreme weather events. Additionally, addressing equity issues, recognizing the water–energy–food nexus, exploring the river as a carbon capture reservoir, and investigating geoengineering concepts are also discussed. The paper concludes with essential research needs and provides recommendations to foster a resilient, sustainable, and equitable Mississippi River and its basin.