Charlotte Harbor is one of major estuaries in Florida. The upper portion of the estuary receives freshwater inflows mainly from the Peace and Myakka Rivers. To study the hydraulic interactions between the Upper Charlotte Harbor (UCH) and its major tributaries, a multi-block model was used to simulate hydrodynamics and salinity transport processes in a simulation domain that includes the UCH, the Lower Peace River (LPR), the Lower Myakka River (LMR), the Shell Creek, and a portion of the Myakkahatchee Creek. In the modeling study, the simulation domain is split into a 3D simulation block and several 2DV blocks. The 3D block includes the UCH and the most downstream portions of the LPR and LMR, while the 2DV blocks contain the rest of the tributaries. All the blocks are patched together without any overlaps. The coupled model solves 3D RANS equations for the 3D block, but laterally averaged RANS equations for the 2DV blocks that consist of narrow and braided tributaries. Both 3D and 2DV sub-models use an efficient semi-implicit, flux-based finite difference method. The dynamic coupling is facilitated using a free-surface correction method, in which matrixes for the water surface correction in both the 3D and 2DV sub-domains are solved simultaneously after they are merged together. Model simulations demonstrated that the multi-block model is an efficient tool for simulating hydrodynamics in a very complex environment and the model application to the LPR-LMR-UCH system is successful.