Prairie-pothole wetlands provide the critical habitat necessary for supporting North American migratory waterfowl populations. However, climate and land-use change threaten the sustainability of these wetland ecosystems. Very few experiments and analyses have been designed to investigate the relative impacts of climate and land-use change drivers, as well as the antagonistic or synergistic interactions among these drivers on ecosystem processes. Prairie-pothole wetland water budgets are highly dependent on atmospheric inputs and especially surface runoff, which makes them especially susceptible to changes in climate and land use. Here, we present the history of prairie-pothole climate and land-use change research and address the following research questions: 1) What are the relative effects of climate and land-use change on the sustainability of prairie-pothole wetlands? and 2) Do the effects of climate and land-use change interact differently under different climatic conditions? To address these research questions, we modeled 25 wetland basins (1949–2018) and measured the response of the lowest wetland in the watershed to wetland drainage and climate variability. We found that during an extremely wet period (1993–2000) wetland drainage decreased the time at which the lowest wetland reached its spill point by four years, resulting in 10 times the amount of water spilling out of the watershed towards local stream networks. By quantifying the relative effects of both climate and land-use drivers on wetland ecosystems our findings can help managers cope with uncertainties about flooding risks and provide insight into how to manage wetlands to restore functionality.