Lakes Volvi and Koronia are located in the Mygdonia basin and constitute the second and fifth largest natural lakes in Greece, respectively. The lakes along with the Mygdonia basin aquifer have undergone severe quantitative and qualitative degradation, while the Lake Koronia has been totally depleted in recent years. In this study, a fully integrated hydrological analysis of the Mygdonia basin for historical and future periods is carried out. Future climatic data were derived and analyzed from a Regional Climate Model, while the implications of climate change on water balance of both lakes and the Mygdonia basin aquifer until 2100 were projected by developing a modelling system which includes coupled hydrological and hydraulic models, such as UTHBAL, MIKE SHE, MIKE HYDRO River and the MIKE HYDRO Basin. The results indicated that the precipitation is expected to decrease by 17%, the temperature to increase by 2.90 °C and as a result, the surface runoff is projected to decrease by 21% and the groundwater recharge to decrease by 38% in the Mygdonia basin at the end of the century. The above changes would have a direct negative impact on the Lakes Koronia and Volvi and the Mygdonia basin aquifer future water balance necessitating adaptation measures.