Levee setbacks are quickly becoming a flagship nature-based solution (NbS) to managing flood risk due to their multiple co-benefits beyond flood management, including nutrient reduction, and groundwater infiltration, and space for recreation. From an ecological perspective, these levee realignments, undertaken by infrastructure agencies like the U.S. Army Corps of Engineers (USACE), are large-scale, high-budget floodplain restorations. However, their conservation benefits are poorly understood. Here, we describe an ongoing, NASA-funded effort leveraging remote sensing, hydrological modeling, artificial intelligence, automated recording units, and field biology to quantify and predict the conservation benefits of levee setback projects along the Lower Missouri River. As one of the USA's largest rivers, this flood-prone system once had a complex, braided channel with diverse floodplain and oxbow habitats, but this was lost to extensive levee buildup in favor of agricultural development and channelization for commercial navigation. As flood regimes change, these levee systems are increasingly failure-prone, prompting tens of millions of dollars of investment in flood control. In the last decade, this has led to several setbacks, including one recently approved South of Omaha, Nebraska. By quantifying habitat cover and the species composition of bird, bat, anuran, and woody plant communities in existing floodplains and setbacks, we are training linked ecological models to predict habitat creation and species conservation benefits from planned and future levee setbacks. This collaborative work will allow USACE and other organizations to account for biodiversity in large-scale water management infrastructure decisions.