There remains much debate regarding the perceived tradeoffs of using freshwater and sediment diversions for coastal restoration in terms of balancing the need for wetland restoration versus preserving eastern oyster (Crassostrea virginica) production. Further complicating the issue, climate change-induced sea-level rise (SLR) and land subsidence are also expected to affect estuarine water quality. In this study, we developed a process-based numerical modeling system that couples hydrodynamic, water quality, and oyster population dynamics. We selected Breton Sound Estuary (BSE) (∼2740 km²) in the eastern Mississippi River Deltaic Plain since it is home to several of the largest public oyster seed grounds and private leases for the Gulf coast. The coupled oyster population model was calibrated and validated against field observed oyster growth data. We predicted the responses of oyster population in BSE to small- (142 m³ s⁻¹) and large-scale (7080 m³ s⁻¹) river diversions at the Caernarvon Freshwater Diversion structure planned in the 2012 Coastal Master Plan (Louisiana) under low (0.38 m) and high (1.44 m) relative sea-level rise (RSLR = eustatic SLR + subsidence) compared to a baseline condition (Year 2009). Model results showed that the large-scale diversion had a stronger negative impact on oyster population dynamics via freshening of the entire estuary, resulting in reduced oyster growth rate and production than RSLR. Under the large-scale diversion, areas with optimal oyster growth rates (>15 mg ash-free dry weight (AFDW) oyster⁻¹ wk⁻¹) and production (>500 g AFDW m⁻² yr⁻¹) would shift seaward to the southeastern edge of the estuary, turning the estuary into a very low oyster production system. RSLR however played a greater role than the small-scale diversion on the magnitude and spatial pattern of oyster growth rate and production. RSLR would result in an overall estuary-wide decrease in oyster growth rate and production as a consequence of decreased salinities in the middle and lower estuary because rising sea level likely causes increased stage and overbank flow downstream along the lower Mississippi River.