Because of the challenges facing today’s society such as the pollution of freshwater systems from intensive agricultural activities, and the interest in how agriculture will be able to cover the ever-increasing nutritional needs of overpopulation with sustainable systems, it is worth paying attention and interest in the management of agricultural watersheds. Agronomic simulation try to provide answers and solutions to these challenges. In this work, the Agricultural Policy Environmental eXtender (APEX) agroecological model is applied to the Karla aquifer in central Greece. The Karla aquifer is currently under intense environmental pressures due to agricultural activity. The APEX model used in combination with the GIS-based interface ArcAPEX combines geomorphology, land use, and soil spatial datasets with the APEX database that contains parameters and settings required to simulate plant growth, runoff, fertilizers applications, tillage operations, irrigation, and their effects at watershed scale. APEX was calibrated (data from 1980 to 2012) and validated (data from 2012 to 2016) for runoff, crop yield, nitrate leaching with satisfactory results. After the calibration and validation process, the APEX model was used to test the impact of different climate scenarios based on mild Regional Climate Pathway (RCP 4.5) on nutrient losses and water quality .