This paper presents the application a 3D hydrodynamic model (EFDC) to Little Manatee River (LMR) estuary located in the southwestern of Tampa Bay. Model boundaries were specified by field observations of hourly observations for model simulations, including freshwater inputs, tides, winds, salinity and temperatures at bay boundary, and air temperatures. By comparison with observations of water levels, salinity, and temperature at several river stations, the hydrodynamic model for LMR river system has been satisfactorily calibrated and verified to support water resources and estuary ecological studies. Salinity intrusions in the river system were investigated under typical low, average, and high flow conditions.