In arid regions, the groundwater drawdown consistently increases, and even for a constant pumping rate, long-term predictions remain a challenge. The present research applies the modular three-dimensional finite-difference groundwater flow (MODFLOW) model to a unique aquifer facing challenges of undefined boundary conditions. Artificial neural networks (ANN) and adaptive neuro fuzzy inference systems (ANFIS) have also been investigated for predicting groundwater levels in the aquifer. A framework is developed for evaluating the impact of various scenarios of groundwater pumping on aquifer depletion. A new code in MATLAB was written for predictions of aquifer depletion using ANN/ANFIS. The geotechnical, meteorological, and hydrological data, including discharge and groundwater levels from 1980 to 2018 for wells in Qassim, were collected from the ministry concerned. The Nash–Sutcliffe efficiency and mean square error examined the performance of the models. The study found that the existing pumping rates can result in an alarming drawdown of 105 m in the next 50 years. Appropriate water conservation strategies for maintaining the existing pumping rate can reduce the impact on aquifer depletion by 33%.