The water supply in the Gaza Strip substantially depends on the groundwater resource of the Gaza coastal aquifer. The climate changes and the over-exploiting processes negatively impact the recovery of the groundwater balance. The climate variability is characterized by the decline in the precipitation of −5.2% and an increase in temperature of +1 °C in the timeframe of 2020–2040. The potential evaporation and the sunshine period are expected to increase by about 111 mm and 5 hours, respectively, during the next 20 years. However, the atmosphere is predicted to be drier where the relative humidity will fall by a trend of −8% in 20 years. The groundwater abstraction is predicted to increase by 55% by 2040. The response of the groundwater level to climate change and groundwater pumping was evaluated using a model of a 20-neuron ANN with a performance of the correlation coefficient (r)=0.95–0.99 and the root mean square error (RMSE)=0.09–0.21. Nowadays, the model reveals that the groundwater level ranges between −0.38 and −18.5 m and by 2040 it is expected to reach −1.13 and −28 m below MSL at the northern and southern governorates of the Gaza Strip, respectively.