A modeling analysis is used to investigate the relative susceptibility of various hydrogeologic configurations to aseismic rupture generation due to deformation of aquifer systems accompanying groundwater pumping. An advanced numerical model (GEPS3D) is used to simulate rupture generation and propagation for three typical processes: (i) reactivation of a preexisting fault, (ii) differential compaction due to variations in thickness of aquifer/aquitard layers constituting the aquifer system, and (iii) tensile fracturing above a bedrock ridge that forms the base of the aquifer system. A sensitivity analysis is developed to address the relative importance of various factors, including aquifer depletion, aquifer thickness, the possible uneven distribution and depth below land surface of the aquifer/aquitard layers susceptible to aquifer-system compaction, and the height of bedrock ridges beneath the aquifer system which contributes to thinning of the aquifer system. The rupture evolution is classified in two occurrences. In one, the rupture develops at the top of the aquifer or at land surface and does not propagate. In the other, the developed rupture propagates from the aquifer top toward the land surface and/or from the land surface downward. The aquifer depth is the most important factor controlling rupture evolution. Specifically, the probability of a significant rupture propagation is higher when the aquifer top is near land surface. The numerical results are processed by a statistical regression analysis to provide a general methodology for a preliminary evaluation of possible ruptures development in exploited aquifer systems susceptible to aquifer-system compaction and accompanying land subsidence. A comparison with a few representative case studies in Arizona, USA, China, and Mexico supports the study outcomes.