The Pampean Plains comprise a flat area of southeastern South America (SESA), encompassing the most populated and productive area of Argentina. Several floods and droughts have been reported in the region during the last 50 years affecting lakeshore villages. In spite of the well-known importance of monitoring hydrological systems in flood-risk areas, long series of instrumental limnimetric data are sparse in the Pampean Plains. Lake Melincué (33°43′S/61°28′W), located in the center of this region, provides a valuable record of the annual lake-area oscillations from 1965 to 2015. In this study we analyze the lake area variability at different time-scales, from intra-annual to multi-annual, investigating the persistence and the frequencies of the series. Our results show that the lake area oscillates following a significant quasi-bidecadal periodicity. A secondary 13 years-frequency signal was detected since the 1970s, when a dramatic increase in Lake Melincué area occurred, associated with a shift to humid conditions in SESA. The analysis of meteorological series suggests that lake area variations are controlled by precipitation and evaporation with different time-lags. Further comparisons of the lake area fluctuations with climate indices from the Pacific and Atlantic oceans provide evidence of the link between the dynamic of lakes in the Pampean Plains and both large-scale climate circulation and low-frequency phenomena. These results confirm that a regular monitoring of these shallow lake systems and the analysis of high-resolution reliable data on inland water environments of the Pampean Plains is fundamental for anticipating their hydrological responses to forecasted climate changes.