Groundwater plays a significant role in domestic, agricultural, and industrial water supply in semi-arid regions. In such areas, rapid growth of population and water demand in conjunction with climate change negatively impacts groundwater quantity and quality. In this research, human activities and climate change effects on groundwater quality in a semi-arid region was studied. First, a numerical groundwater model was calibrated as a tool for simulating an aquifer system. Then, groundwater salinity, as a measure of water quality, was simulated using the Gene Expression Programming ‘GEP’ algorithm. In order to identify major factors influencing the salinity, the Grey Relational Analysis (GR) technique was adopted. Furthermore, in the case study of Mahabad aquifer in northwestern Iran, decreasing precipitation has reduced river flow and aquifer recharge. Crop pattern change, through groundwater exploitation and irrigation return flow, impacted groundwater quality. Changes in temperature, evaporation and crop water requirement has also influenced the surface water-groundwater budget in the region. Groundwater simulations showed a decreasing trend in groundwater level while GEP analysis demonstrated that groundwater electrical conductivity (EC) increased over the past 40 years. Finally, GRA application showed that groundwater withdrawal and agricultural return flow had the highest correlation with increasing EC, compared with the effect of precipitation and temperature as climatic factors.