A highly parameterized variable-density groundwater flow and solute transport model was developed to test multiple hypotheses for upward movement of treated wastewater (effluent) injected into a saline coastal aquifer in southeastern Florida, USA. The model was designed to assess risk to a drinking-water aquifer above the zone of injection, where monitoring wells have detected effluent. The model-based analysis accommodated geological and data complexity, including the observed presence of effluent in upper monitoring wells, but not in lower monitoring wells, thereby giving the appearance of the effluent having bypassed geological layers. The modeling approach included the application of multiple methodologies to reduce model run times during parameter estimation while providing detailed calibrated model(s) that can be used to assess the potential capacity for different mechanisms of effluent migration. The methods included use of a semi-analytical equation to quickly calculate initial concentrations, parallelization of model runs over multiple processors when calibrating, and utilization of the concepts of singular value decomposition and Tikhonov regularization to accommodate a high level of parameterization complexity. The results reveal that vertical effluent migration could occur as diffuse flow through heterogeneous confining units; however, flow through a channelized pathway caused by well construction appears to be more likely.