The Aculeo Lake is an important natural reservoir of Central Chile, which provides valuable ecosystem services. This lake has suffered a rapid shrinkage of the water levels from year 2010 to 2018, and since October 2018, it is completely dry. This natural disaster is concurrent with a number of severe and uninterrupted drought years, along with sustained increases in water consumption associated to land use/land cover (LULC) changes. Severe water shortages and socio-environmental impacts were triggered by these changes, emphasizing the need to understand the causes of the lake desiccation to contribute in the design of future adaptation strategies. Thereby, the Water Evaluation and Planning (WEAP) hydrological model was used as a tool to quantify the water balance in the catchment. The model was run under a combination of three land use/land cover and two different climate scenarios that sample the cases with and without megadrought and with or without changes in land use. According to the results, the main triggering factor of the lake shrinkage is the severe megadrought, with annual rainfall deficits of about 38%, which resulted in amplified reductions in river flows (44%) and aquifer recharges (24%). The results indicate that the relative impact of the climate factor is more than 10 times larger than the impact of the observed LULC changes in the lake balance, highlighting the urgent need for adaptation strategies to deal with the projected drier futures.