Navigating trade-offs between meeting societal water needs and supporting functioning ecosystems is integral to river management policy. Emerging frameworks provide the opportunity to consider multiple river uses explicitly, but balancing multiple priorities remains challenging. Here we quantify relationships between hydrologic regimes and the abundance of multiple native and nonnative fish species over 18 years in a large, dryland river basin in southwestern United States. These models were incorporated into a multi-objective optimization framework to design dam operation releases that balance human water needs with the dual conservation targets of benefiting native fishes while disadvantaging nonnative fishes. Predicted designer flow prescriptions indicate significant opportunities to favor native over nonnative fishes while rarely, if ever, encroaching on human water needs. The predicted benefits surpass those generated by natural flow mimicry, and were retained across periods of heightened drought. We provide a quantitative illustration of theoretical predictions that designer flows can offer multiple ecological and societal benefits in human-altered rivers.