Lakes in the Mediterranean climate zone experience high variation in rainfall and are vulnerable to changes in climate, land cover and anthropogenically induced effects on water level and salinity. This paper presents the results from the analyses of spatiotemporal changes of land cover/uses at catchment scale of two connected lakes in Greece that have recently exhibited a dramatic loss of water volume, and investigates the potential role of climate change as a main driver of the lake water loss. The classification of the historical land cover/uses was based on a series of LANDSAT images from 1972 to 2011. Changes in the landscape structure were assessed using landscape metrics that were calculated with FRAGSTATS software. Climate data and temporal series of water level, conductivity and chloride concentration, were analyzed to investigate the potential role of climate variability to the lake hydrology and water quality. The results showed that between 1972 and 2011 almost 28% of Lake Vegoritis and 13% of Lake Petron were replaced by cultivations and reed beds. Landscape metrics showed that the lake catchment’s area is highly fragmented, indicating a heterogeneous spatial pattern and degradation of the rural habitats. Regarding the climatic factors, it appears that precipitation follows a declining trend correlating with water level fluctuations. The water level in Lake Vegoritis also correlated with the conductivity and chloride concentration, indicating a relationship between hydrological alteration and water quality. Overall, a combined effect of climate- and human-induced land cover changes appeared to be responsible for the drastic environmental changes that urge the need for implementing effective restoration and mitigation measures.