This study explores a general framework for quantifying anthropogenic influences on groundwater budget based on normalized human outflow (hout) and inflow (hin). The framework is useful for sustainability assessment of groundwater systems and allows investigating the effects of different human water abstraction scenarios on the overall aquifer regime (e.g., depleted, natural flow-dominated, and human flow-dominated). We apply this approach to selected regions in the USA, Germany and Iran to evaluate the current aquifer regime. We subsequently present two scenarios of changes in human water withdrawals and return flow to the system (individually and combined). Results show that approximately one-third of the selected aquifers in the USA, and half of the selected aquifers in Iran are dominated by human activities, while the selected aquifers in Germany are natural flow-dominated. The scenario analysis results also show that reduced human withdrawals could help with regime change in some aquifers. For instance, in two of the selected USA aquifers, a decrease in anthropogenic influences by ~20% may change the condition of depleted regime to natural flow-dominated regime. We specifically highlight a trending threat to the sustainability of groundwater in northwest Iran and California, and the need for more careful assessment and monitoring practices as well as strict regulations to mitigate the negative impacts of groundwater overexploitation.