In many regions, long-term drought is altering patterns of water use and reservoir storage, which in turn can facilitate the spread of non-native fishes. Decreasing supply and increasing demand in USA’s Colorado River basin has reduced water storage in the country’s two largest reservoirs. In 2022, historically low water levels in Lake Powell and associated fish entrainment and warming of release temperatures led to the first observations of non-native Smallmouth Bass (Micropterus dolomieu) reproduction in the Grand Canyon segment of the Colorado River downstream from Lake Powell. These piscivorous fish have the potential to threaten federally listed fish species. In response to this invasion, several management strategies have been implemented including mechanical removal of Smallmouth Bass and water storage/dam operations designed to decrease release temperatures to reduce the risk of reproduction, growth, and establishment. To assist managers confronting this Smallmouth Bass range expansion, we developed a matrix-based stage-structured population model to forecast the effects of different suppression scenarios, while accounting for different sources of uncertainty in demographic rates including dispersal dynamics and recruitment, sensitivity to environmental conditions, operational uncertainties associated with control options, and uncertainty related to future climate and basin-wide hydrology and water management strategies. The objectives of our study were 1) to simulate and compare the effectiveness of different prevention and suppression actions, and 2) assess the importance of sources of uncertainty related to the rate and drivers of the invasion to inform future research. Our simulations predict high risk of Smallmouth Bass establishment throughout Grand Canyon under low reservoir levels despite varying levels of suppression; however, higher reservoir water levels or cold-water releases are predicted to stop population growth under most hydrological scenarios. Understanding the sources of uncertainty in invasion dynamics can assist managers in developing response strategies, future monitoring, and research to inform resource management.