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The widespread fish kills of Gulf menhaden (Brevoortia patronus) were reported beginning on 7/31/2015 in the Cotton Bayou, Orange Beach City, Alabama. Although some possible reasons for the fish kill event were provided (e.g., high water temperature, low wind speed, low dissolved oxygen, and so on), there were no existing water quality models to show when the assumed low dissolved oxygen condition could happen and what environmental factors affect/control the water quality condition. Therefore, a quantitative analysis was done to simulate salinity, water temperature, dissolved oxygen temporal and spatial distributions and their internal reciprocal linking by developing a three dimensional hydrodynamic and water quality model using EFDC (Environmental Fluid Dynamics Code) for the Perdido and Wolf Bay system including the Cotton Bayou. The external driving forces include the freshwater inflows into the study area, atmospheric variables, and the astronomical tides contributing/affecting hydrodynamic and the heat exchange. The model was validated using statistical parameters to assess the accuracy against observed data. The simulated hydrodynamic and water quality parameters (water temperature, salinity and dissolved oxygen) had reasonable agreements with the observed data. Simulation results in the Cotton Bayou were analyzed to diagnose the fish kill that could happen in 2015. Through the sensitivity analysis, it was found that the chemical oxygen demand, sediment oxygen demand, and wind speed could have a large effect on the vertical distribution of the dissolved oxygen, especially for the shallow water region. The model was also further used to examine how the system responds to the future climate change (sea level rise and air temperature increase under the global warming projection). Future air temperature increase is projected to reduce dissolved oxygen but the sea level rise can increase the mixing and then the dissolved oxygen.