Despite human-induced changes in floodplains over the past century, comprehensive data of long-term land use change within floodplains of large river basins are limited. Data of long-term and large-scale floodplain land use are required to effectively quantify floodplain functions and development trajectories. They also provide a holistic perspective on the future of floodplain management and restoration – and concomitantly flood-risk mitigation. Here, we present the first available dataset that provides spatially explicit estimates of land use change along the floodplains of the Mississippi River Basin (MRB) covering 60 years (1941-2000) at a 250-m resolution. We derived this MRB floodplain land use change dataset from two input data sources: (i) the high-resolution global floodplain extent dataset GFPLAIN250m, and (ii) the annual FOREcasting SCEnarios of Land-use Change (FORE-SCE) dataset for the continental United States. Our results suggest that MRB floodplains have transitioned irreversibly from natural ecosystems to predominantly agricultural land use (e.g., more than 10,000 km² of wetlands have been lost due to agricultural expansion). Developed land use within the floodplain has also steadily increased. The dataset is publicly available through HydroShare: https://gishub.org/mrb-data as well as an interactive online map interface: https://gishub.org/mrb-floodplain. These products will support MRB resilience and sustainability goals by advancing data-driven decision making on floodplain restoration, buyout, and conservation scenarios.