We use mathematical and numerical modeling techniques to evaluate overpressure resulting from topographic-driven flow in the Mississippi Embayment and discuss potential implications for wave propagation and seismic hazards in the New Madrid seismic zone (nmsz). The mathematical model implies that the magnitude of excess pore pressure in the discharge area is determined by a basin’s geometry and the hydraulic conductivity of basin strata. Our modeling results explain how excess pore pressures can be sustained in a wide discharge area of the nmsz by regional gravity flow. When a vertical fault zone is included in the model, the predicted magnitude of excess pressure is generally consistent with observed elevation heads (10–30 m) of artesian wells that penetrate the Upper Cretaceous and Paleozoic aquifers in the basin. The modeling results demonstrate that overpressures developed in Cambrian-Silurian carbonate rocks in the central embayment could be communicated to shallower layers if basin-wide confining units are locally breached by faults. We suggest that the stratigraphic conditions responsible for overpressure development may significantly influence the hydrologic response of the basin during large earthquake events.