Lakes in the Southeastern Pampa plain (SEPP) are highly sensitive to environmental changes. Paleoenvironmental studies in these lakes have reconstructed climate and hydrological changes from the Early Holocene to the present. These reconstructions are based on compositional and taphonomic analyses of biological proxies, including diatoms, molluscs, pollen, non-pollen palynomorphs, plant macroremains, and associated fauna. Seven lacustrine records, Lagunas Nahuel Rucá, Hinojales-San Leoncio, Lonkoy, Tobares, Hinojales, La Brava, and Kakel Huincul were studied and discussed within a regional context. This synthesis revealed that external climatic triggers, alongside intrinsic limnological processes, were the primary drivers of paleoenvironmental changes affecting these lakes over the last 12,000 years. During the Early Holocene, the SEPP experienced a dry climate, drier than that of the Late Pleistocene-Holocene transition, emphasizing the significant role of precipitation changes on lake dynamics. The Middle Holocene saw even drier conditions, leading to the desiccation of some lakes (e.g., Laguna Tobares), while others remained active due to groundwater inputs during the marine transgressive–regressive cycle. In the last 2500 years, increased rainfall led to more freshwater input, giving lakes their modern configurations by 600 years BP. Since 1670 CE, human activities have increasingly impacted these lakes, significantly enhancing eutrophication over the last 25 years.