St. Louis Bay estuary is a vital water body in the Mississippi Gulf Coast Region and greatly affects the water quality in the Mississippi Sound. As the first step of total maximum daily load (TMDL) study, a hydrodynamics model was developed by integrating Hydrological Simulation Program Fortran (HSPF) and Environmental Fluid Dynamics Code (EFDC). In this application the EFDC model was configured to simulate time-varying surface water elevation, velocity, salinity, and water temperature. The HSPF was applied to compute the fresh water discharge from the upstream watersheds. The model reasonably simulated the tidal range and phase. The simulated water temperature and salinity showed good and fairly good agreement with observations. The calculated correlation coefficients between computed and observed velocity were lower compared with those for water level, temperature, and salinity, but the magnitudes of simulated velocity were found to be in the range of observed data. The wind data was found to have strong impacts on velocity simulation by modeling verification tests. Near the study area, there is wind data available only at one station, which has been applied to the entire modeling domain. The lack of high-resolution wind data makes it very difficult to simulate the velocity distribution well. It is anticipated and recommended that the development of this model be continued to synthesize additional field data into the modeling process.