This study presents the projected future evolution of water resource balance and nitrate pollution under various climate change scenarios and climatic models using a holistic approach. The study area is Almyros Basin and its aquifer system, located in Central Greece, Thessaly, Greece. Almyros Basin is a coastal agricultural basin and faces the exacerbation of water deficit and groundwater nitrate pollution. Using an Integrated Modeling System (IMS), which consists of the surface hydrology model (UTHBAL), the nitrate leachate model (REPIC, an R-ArcGIS-based EPIC model), the groundwater hydrology model (MODFLOW), and the nitrates’ advection, dispersion, and transport model (MT3MDS), the projected values of the variables of water quantity and quality are simulated. Nineteen climatic models from the Med-CORDEX database were bias-corrected with the Quantile Empirical Mapping method and employed to capture the variability in the simulated surface and groundwater water balance and nitrate dynamics. The findings indicate that future precipitation, runoff, and groundwater recharge will decrease while temperature and potential evapotranspiration will increase. Climate change will lead to reduced nitrogen leaching, lower groundwater levels, and persistent nitrate pollution; however, it will be accompanied by high variability and uncertainty, as simulations of IMS under multiple climatic models indicate.