The Himalayan, Karakoram, and Hindu Kush (HKH-TMHA) are the three main mountain ranges in the high-mountain Asia region, covering the China–Pakistan Economic Corridor (CPEC). In this study, we identified glacial lakes in the HKH-TMHA region based on multitemporal Landsat images taken from 1990 to 2020. We analyzed the spatial distribution and evolution of glacial lakes in the HKH-TMHA region from the perspective of their elevation, size, and terrain aspect; then, we described their temporal changes. The results showed that approximately 84.56% of the glacial lakes (84.1% of the total lake area) were located at elevations between 4000 m and 5500 m, and glacial lakes with areas ranging from 0.01–0.5 km2 accounted for approximately 95.21% of the number and 63.01% of the total area of glacial lakes. The number (38.64%) and area (58.83%) of south-facing glacial lakes were largest in HKH-TMHA and expanded significantly over time. There were 5835 (664.84 ± 89.72 km2) glacial lakes in 1990; from 1990 to 2020, the number of glacial lakes in the HKH-TMHA region increased by 5974 (408.93 km2) in total; and the annual average increase in the area of glacial lakes reached 13.63 km2 (11.15%). In 2020, the total number of glacial lake reached to 9673 (899.66 ± 120.63 km2). In addition, most glacial lakes were located in the Eastern Himalayan, China, and the Indus Basin. Based on the precipitation and temperature analyses performed in our study area, we found inconsistent climate characteristics and changes in the three mountain ranges. In general, the daily precipitation (temperature) increased by 1.0766 mm (1.0311 °C), 0.8544 mm (0.8346 °C), and 0.8245 mm (−0.1042 °C) on the yearly, summer, and winter scales, respectively. Glacial melting and climate change are common contributors to glacial lake expansion. The investigation of glacial lakes in this region can provide basic supporting data for research on glacial lake-related disasters, land cover, and climate change in the high-mountain Asia region.