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Variations in freshwater inflow have ecological consequences for estuaries ranging among eutrophication, flushing and transport, and high and low salinity impacts on biota. Predicting the potential effects of the magnitude and composition of inflow on estuaries over a range of spatial and temporal scales requires reliable mathematical models. The goal of this study was to develop and test a model of ecosystem processes with variable freshwater inflow to the sub-tropical Caloosahatchee River Estuary (CRE) in southwest Florida from 2002 to 2009. The modeling framework combined empirically derived inputs of freshwater and materials from the watershed, daily predictions of salinity, a box model for physical transport, and simulation models of biogeochemical and seagrass dynamics. The CRE was split into 3 segments to estimate advective and dispersive transport of water column constituents. Each segment contained a sub-model to simulate changes in the concentrations of organic nitrogen and phosphorus (ON and OP), ammonium (NH 4 + ), nitrate-nitrite (NO x − ), ortho-phosphate (PO 4 −3 ), phytoplankton chlorophyll a (CHL), and sediment microalgae (SM). The seaward segment also had sub-models for seagrasses ( Halodule wrightii and Thalassia testudinum ). The model provided realistic predictions of ON in the upper estuary during wet conditions since organic nitrogen is associated with freshwater inflow and low salinity. Although simulated CHL concentrations were variable, the model proved to be a reliable predictor in time and space. While predicted NO x − concentrations were proportional to freshwater inflow, NH 4 + was less predictable due to the complexity of internal cycling during times of reduced freshwater inflow. Overall, the model provided a representation of seagrass biomass changes despite the absence of epiphytes, nutrient effects, or sophisticated translocation in the formulation. The model is being used to investigate the relative importance of colored dissolved organic matter (CDOM) vs. CHL in submarine light availability throughout the CRE, assess if reductions in nutrient loads are more feasible by controlling freshwater quantity or N and P concentrations, and explore the role of inflow and flushing on the fates of externally and internally derived dissolved and particulate constituents. [ABSTRACT FROM AUTHOR]