The water quality of a waterbody is determined by internal hydrodynamic processes as well as external loadings. Understanding the interaction between the external loading and internal process of a waterbody is essential for efficient water management and water quality improvement. Studies and efforts have focused on water and nutrient loading from drainage watersheds, but the contribution of the waterbody's internal process to water quality is often ignored and not well documented. This study investigated how the water quality of Lake Okeechobee is controlled by external and internal factors using statistical and numerical modeling approaches. Water quantity and quality observed at the outlets of the Lake Okeechobee drainage basins and 19 monitoring sites located within the lake were statistically analyzed using multilinear regression. A three-dimensional numerical model, namely Environmental Fluid Dynamics Code (EFDC), was calibrated to the observations to mathematically represent the lake's internal hydrodynamic process. The multilinear regression found that the water quality was the most sensitive to air temperature, the total phosphorus (TP) concentration of inflow entering the lake from the Kissimmee River basins, and the amount of outflow discharged from the lake among external factors. However, the regression models and their explanatory power were substantially varied by the monitoring stations. The model parameter sensitivity analysis of the calibrated EFDC model showed that model parameters related to the lake's internal algal processes including algal growth, predation, and basal metabolism rates had greater impacts on algal biomass than other model parameters controlling nutrient-related processes such as nutrient half-saturation and hydrolysis rates. The EFDC input data sensitivity analysis found that wind (speed) is the major driving force for the internal hydrodynamic processes; its impact on algal biomass was greater than those of the external loadings. In addition, the algal biomass was found to have an inverse relationship with wind-induced horizontal currents. The results demonstrate the dynamic contribution of the internal and external drivers to the water quality of Lake Okeechobee, suggesting the need to consider both internal hydrodynamic and external loading processes for efficient water quality improvement of the lake.