Lakes in the Hindu Kush-Himalaya-Tibetan (HKHT) regions are crucial indicators for the combined impacts of regional climate change and resultant glacier retreat. However, they lack long-term systematic monitoring and thus their responses to recent climatic change still remain only partially understood. This study investigated lake extent fluctuations in the HKHT regions over the past 40 years using Landsat (MSS/TM/ETM+/OLI) images obtained from the 1970s to 2014. Influenced by different regional atmospheric circulation systems, our results show that lake changing patterns are distinct from region to region, with the most intensive lake shrinking observed in northeastern HKHT (HKHT Interior, Tarim, Yellow, Yangtze), while the most extensive expansion was observed in the western and southwestern HKHT (Amu Darya, Ganges Indus and Brahmaputra), largely caused by the proliferation of small lakes in high-altitude regions during 1970s–1995. In the past 20 years, extensive lake expansions (~39.6% in area and ~119.1% in quantity) were observed in all HKHT regions. Climate change, especially precipitation change, is the major driving force to the changing dynamics of the lake fluctuations; however, effects from the glacier melting were also significant, which contributed approximately 31.9–40.5%, 16.5–39.3%, 12.8–29.0%, and 3.3–6.1% of runoff to lakes in the headwaters of the Tarim, Amu Darya, Indus, and Ganges, respectively. We consider that the findings in this paper could have both immediate and long-term implications for dealing with water-related hazards, controlling glacial lake outburst floods, and securing water resources in the HKHT regions, which contain the headwater sources for some of the largest rivers in Asia that sustain 1.3 billion people.