Lakes, either artificial or natural, are greatly important as a component in their catchments’ hydrology, but also as ecosystem service providers. However, due to climate change, they have begun to face numerous problems with their water quality and quantity. Furthermore, general circulation models (GCMs) show future climate change with a reduction in rainfall and increase in temperature. The aim of the current study is to present an application where GCMs and state-of-the-art hydrological modelling system MIKE SHE/MIKE 11 are combined for assessing the response of a Greek lake in terms of its water balance and water level under climate change. Four general circulation models (GCMs; GFDL-CM3, MIROC-ESM-CHEM, MIROC-ESM, IPSL-CM5A-LR) for the extreme climate change scenario of RCP8.5 were used in the basin of Lake Zazari in Greece as a case study. Results showed that, by keeping the irrigated demands (the main water user) unchanged in the future, the lake exhibited a lower water level for all GCMs, fluctuating from −0.70 to −1.8 m for the mean (min) water level and from −0.30 to −1.20 m for the mean (max) water level. Instead of the above and by preserving the amount of withdraw water n from the lake at a certain percentage of inflows, the irrigated area should be reduced from 54.1% to 64.05% depending on the circulation model.