Hydrodynamics, salinity transport processes, and thermodynamics in Charlotte Harbor and its major tributaries in Florida, USA were simulated using a coupled three-dimensional (3D) and laterally averaged two-dimensional (2DV) hydrodynamic model named UnLESS, in support of the re-evaluation of minimum freshwater inflows for two water bodies in the system, namely the lower Peace River (LPR) and lower Shell Creek (LSC). The UnLESS model involves a dynamic and two-way coupling of the 3D unstructured Cartesian grid model UnLESS3D (Chen, 2011) with the laterally averaged model LAMFE (Chen, 2003a) using a semi-implicit scheme named the free-surface correction (FSC) method (Chen, 2003b.)The simulation period was January 2013 through August 2014, during which best real-time data of water elevation, current, salinity, and temperature at five measurement stations within the simulation domain were available. Comparisons of model results with these real-time field data show that UnLESS is capable of simulating hydrodynamics, salinity transport processes, and thermodynamics well in the Charlotte Harbor estuary. Good matches of model results with measured data suggest that both estimated ungauged flows and downstream boundary conditions were reasonable. Major physical characteristics in the Charlotte Harbor system are correctly simulated by the UnLESS model. It is demonstrated that the dynamically coupled 3D-2DV model UnLESS is robust and very efficient for complex systems such as Charlotte Harbor, which has a large waterbody with islands and several narrow and meandering tributaries.