Large floodplain-river ecosystems are often highly modified to provide services that society desires, yet these modifications can limit an ecosystem’s ability to adapt to changing conditions. The adaptive capacity of an ecosystem, its general resilience, is a conceptual framework for considering how a system will respond to such changes. We sought to apply aspects of three general resilience principles (diversity and redundancy, connectivity, and controlling variables) to our understanding of floodplain-river ecosystem structure and function. We demonstrate the applicability of this approach in a case study of the Upper Mississippi River System (UMRS). In doing so, we developed ten indicators that highlight important structural and functional aspects of this floodplain-river ecosystem, and likely underlie the capacity of large rivers to cope with environmental change and disturbance. We developed diversity and redundancy indicators for aquatic habitats, patterns of floodplain inundation, and fish communities. Connectivity indicators included metrics of longitudinal and lateral connections. Controlling variable indicators included deviations from historic water surface elevation fluctuations, water clarity, nutrient concentrations, and aquatic invasive species. This set of indicators provides a simple description of the adaptive capacity of four distinct reaches of the UMRS: Upper Impounded, Lower Impounded, Unimpounded Reaches of the Upper Mississippi River and the entire Illinois River. High aquatic habitat diversity and redundancy, fish functional diversity and redundancy, and water clarity, and the scarcity of invasive fish species are all factors that likely contribute to the high general resilience of the Upper Impounded Reach. However, the limited longitudinal connectivity and establishment of a minimum water level for navigation are factors that may inhibit the general resilience of this reach. In the Lower Impounded Reach, there is high within-reach variability for individual indicators such as aquatic habitat diversity, fish functional diversity and redundancy, and longitudinal and lateral connectivity. In the Unimpounded Reach, a high degree of longitudinal connectivity likely enhances its general resilience, but low aquatic habitat diversity, low lateral connectivity, and relatively high number of invasive fish species inhibit general resilience. For the Illinois River Reach, the relatively high fish functional diversity and redundancy likely contributes to its general resilience, whereas high number of invasive fish species, low water clarity, low lateral connectivity, and high range of water levels may inhibit general resilience. Indicators derived from application of concepts of general resilience provide insight into the current coping capacity of the UMRS and identify opportunities for enhancing resilience.