The Altiplano-Puna Plateau holds several shallow lakes, which are very sensitive to climate changes. This work is focused on a high-altitude lake system called Lagunas de Vilama (LVS), located in a complex climatic transition area with scarcity of continuous and homogeneous instrumental records. The objective of this study is to determine the regional spatial–temporal variability of precipitation and evaluate the seasonal and interannual lake responses. We use a lake-surfaces record derived from Landsat images to investigate links with regional precipitations and different climatic forcings. The results reveal that austral summer and autumn precipitations control the variability of the annual lake-surfaces. Also, we found intra-annual and interannual lags in the lake responses to precipitations, and identified several wet and dry stages. Our results show negative trends in precipitations and lake-surfaces, whose were strengthened by a shift to a warm phase of the Atlantic Multidecadal Oscillation in the 1990s. The El Niño Southern Oscillation, Pacific Decadal Oscillation, and Southern Annular Mode also exert a strong influence in the region. This study demonstrates that the variability of LVS lakes is strongly related to the South American Monsoon System dynamics and large-scale climate forcings from the Pacific and Atlantic Oceans. This work provides novel indices which demonstrated to be good indicators of regional hydro-climatological variability for this region of South America.