Eastern oysters growing in deltaic Louisiana estuaries in the northern Gulf of Mexico must tolerate considerable salinity variation from natural climate variability (e.g., rainfall and stream run-off pushing isohalines offshore; tropical storms pushing isohalines inshore) and man-made diversions and siphons releasing freshwater from the Mississippi River. These salinity variations are predicted to increase with future climate change because of the increased frequency of stronger storms and also in response to proposed large-scale river diversions. Increased Mississippi River flow into coastal estuaries from river diversions, along with potential changes in rainfall and stream run-off from climate change will alter spatial and temporal salinity patterns. In this study we used an individual Dynamic Energy Budget model to predict growth and reproductive potential of eastern oysters across observed and simulated salinity gradients corresponding to different climate and river management scenarios. We used validated model outputs of salinity from a coupled hydrology-hydrodynamic model to assess the current impacts of Davis Pond diversion discharge on oysters located downstream. Under a high diversion discharge scenario oyster growth potential was reduced by 9%, 4%, and 1% in Upper, Mid, and Lower Bay locations, respectively, as compared to a limited discharge year. Reproductive outputs decreased by 34% and 2% in the Upper and Lower Bay locations, respectively, and increased by 2% at the Mid Bay site. In scenarios combining predicted increased temperature with the effect of diversions, all oysters located in the Upper and Mid Bay sites died due to severe summer conditions (high temperatures combined with low salinity). Overall, oysters in down-estuary locations, influenced by both estuarine river management and gulf conditions demonstrated significant tolerance to changing salinity and temperature conditions from diversions alone and when combined with climate change. In contrast, oysters located up-estuary, and exposed to more extreme salinity impacts from river management, demonstrated potentially lethal impacts through direct mortality, and reduced sustainability through decrease in reproductive output. These predictions at the individual level may translate into less sustainable populations in the most extreme scenarios; restoration and production plans may benefit from accounting for these impacts on reproductive output particularly as decision makers seek to restore critical oyster areas.