Lake Vanda is a perennially ice-covered, meromictic, endorheic lake located in the McMurdo Dry Valleys of Antarctica, and an exceptional sentinel of climate change within the region. Lake levels rose 15 m over the past 68 years in response to climate-driven variability in ice-cover sublimation, meltwater production, and annual discharge of the Onyx River, the main source of water to the lake. Evidence from a new bathymetric map and water balance model combined with annual growth laminations in benthic mats suggest that the most recent filling trend began abruptly 80 years ago, in the early 1930s. This change increased lake volume by > 50%, triggered the formation of a new, upper, thermohaline convection cell, and cooled the lower convection cell by at least 2 °C and the bottom-most waters by at > 4 °C. Additionally, the depth of the deep chlorophyll a maximum rose by > 2 m, and deep-growing benthic algal mats declined while shallow benthic mats colonized freshly inundated areas. We attribute changes in hydrology to regional variations in air flow related to the strength and position of the Amundsen Sea Low (ASL) pressure system which have increased the frequency of down-valley, föhn winds associated with surface air temperature warming in the McMurdo Dry Valleys. The ASL has also been implicated in the recent warming of the Antarctic Peninsula, and provides a common link for climate-related change on opposite sides of the continent. If this trend persists, Lake Vanda should continue to rise and cool over the next 200 years until a new equilibrium lake level is achieved. Most likely, future lake rise will lead to isothermal conditions not conducive to thermohaline convection, resulting in a drastically different physical, biogeochemical, and biological structure than observed today.