This bill establishes the Mississippi River Restoration and Resilience Initiative, a federal program designed to protect and restore the ecological health of the Mississippi River and its surrounding areas across ten states: Arkansas, Illinois, Iowa, Kentucky, Louisiana, Minnesota, Mississippi, Missouri, Tennessee, and Wisconsin. The bill creates a new Mississippi River National Program Office within the Environmental Protection Agency, headed by a director who will coordinate restoration efforts across federal agencies and non-federal partners. The initiative focuses on five main areas: improving water quality, building community resilience against flooding, protecting fish and wildlife habitat, preventing invasive species, and conducting scientific research and monitoring. The EPA director must develop measurable goals within one year and an action plan within two years, with updates every five years, while also establishing three research centers affiliated with the U.S. Geological Survey to support the work. The bill authorizes federal funding for eligible projects carried out by government agencies, nonprofits, universities, and tribal governments, with most non-federal entities required to contribute at least 20 percent of project costs, though tribal governments and community capacity-building projects receive full federal funding.