Recent studies suggest Asian Water Tower (AWT) is vulnerable to climate change with a detrimental effect on water and food security. Comprehensive information about the spatio-temporal variability of lakes, an important freshwater resource, is lacking. Therefore, we analyzed 89,480 Landsat images to examine the change in the lakes size around AWT between 1977±2 and 2020±2. Sequentially, the trends of precipitation, snow water equivalent, glacier mass, and permafrost were analyzed to understand what caused the lake’s alteration. According to our findings, from 1977±2 to 2020±2, 84% of mapped lakes grew during the wet season, whereas 81% of the lakes grew during the dry season. Lakes in the Inner TP and Tarim Interior basins expanded dramatically. The Helmand, Amu Darya, and Yangtze basins are the primary locations of shrinking lakes. The Aral Sea shrunk by 90%. From the region as a whole, the alpine lakes showed a shrinking trend and the plain lakes showed an expanding trend from 1977±2 to 1990±2, and vice versa from 1990±2 to 2020±2. Glacial loss and permafrost thawing were corresponding to lake expansion in the Inner TP, Tarim Interior, Syr Darya, and Mekong basins. Permafrost discontinuities may cause Indus and Ganges to not grow significantly in lakes with increased recharge to the basin. Extreme droughts depleted the lake in Helmand. Human intervention have caused the shrinking of the Aral Sea and the lakes in the lower Yangtze River. As AWT retreats and feeds lakes, we need to take immediate action for managing risks and adaption.