Freshwater and sediment management in estuaries affects water quality, particularly in deltaic estuaries. Furthermore, climate change-induced sea-level rise (SLR) and land subsidence also affect estuarine water quality by changing salinity, circulation, stratification, sedimentation, erosion, residence time, and other physical and ecological processes. However, little is known about how the magnitudes and spatial and temporal patterns in estuarine water quality variables will change in response to freshwater and sediment management in the context of future SLR. In this study, we applied the Delft3D model that couples hydrodynamics and water quality processes to examine the spatial and temporal variations of salinity, total suspended solids, and chlorophyll-α concentration in response to small (142 m³ s⁻¹) and large (7080 m³ s⁻¹) Mississippi River (MR) diversions under low (0.38 m) and high (1.44 m) relative SLR (RSLR = eustatic SLR + subsidence) scenarios in the Breton Sound Estuary, Louisiana, USA. The hydrodynamics and water quality model were calibrated and validated via field observations at multiple stations across the estuary. Model results indicate that the large MR diversion would significantly affect the magnitude and spatial and temporal patterns of the studied water quality variables across the entire estuary, whereas the small diversion tends to influence water quality only in small areas near the diversion. RSLR would also play a significant role on the spatial heterogeneity in estuary water quality by acting as an opposite force to river diversions; however, RSLR plays a greater role than the small-scale diversion on the magnitude and spatial pattern of the water quality parameters in this deltaic estuary.