This bill establishes the Mississippi River Restoration and Resilience Initiative (MRRRI) , a nonregulatory program aimed at protecting and restoring the ecological health and resilience of the Mississippi River for current and future generations, as well as its fish and wildlife. The initiative will be managed by a new Mississippi River National Program Office within the Environmental Protection Agency (EPA), located in one of the ten Mississippi River States. The MRRRI Director, appointed by the EPA Administrator, will coordinate actions, develop and implement actionable goals and an action plan, and ensure engagement with Tribal governments and other stakeholders. A dedicated Tribal Liaison will facilitate communication and coordination with Tribal entities. The Director is also responsible for annual reports to Congress detailing progress and funding utilization. Projects and activities under the MRRRI must address at least one of several focus areas, including improving water quality, enhancing community resilience against floods, protecting and restoring fish and wildlife habitat, preventing aquatic invasive species, and supporting related communication and scientific data collection. Eligible actions range from restoring natural hydrologic functions and removing structures to reducing nonpoint source pollution, cleaning up legacy contaminants, and building community capacity for restoration efforts. The bill mandates the development of measurable actionable goals and a comprehensive action plan, to be updated every five years, guiding the initiative's projects and activities. To support these efforts, the Secretary of the Interior will establish a network of three Mississippi River Corridor Research Centers within the United States Geological Survey, including a National Center and two regional centers. These centers will conduct scientific research, advise Federal agencies, and collaborate on restoration and resiliency efforts, informed by a Mississippi River science forum and a subsequent science plan. Funding for the MRRRI can be transferred to relevant Federal agencies or awarded as grants to non-Federal entities, with a specific allocation for Tribal governments and organizations. While the Federal share for most projects is 80 percent, projects carried out by Tribal governments or focused on community capacity building receive 100 percent Federal funding. The initiative is designed to supplement, not supplant, existing environmental laws and programs, including the functions of the Hypoxia Task Force.