As one of the most important reservoirs of water in arid regions, lakes experience a series of complicated changes. However, the natural driving mechanisms behind such changes remain unclear. In this study, we collected data from 1333 lakes in the arid region of Central East Asia (CEA) to investigate the underlying natural causes of lake changes over the past five decades. The lakes were located within three different geomorphological zones: (I) Tibetan Plateau zone; (II) high mountain—basin zone; and (III) low mountain zone. Our results show that lakes as a whole in CEA exhibit a unique change trend, with an overall lake area increase of 7099 km² (41%) and with heterogeneous spatial variations over the past five decades. The lake area increase was 6236 km² (47%), 935 km² (31%) and decrease was 72 km² (~1%) in zones I, II, and III, respectively. The different geomorphological zones have influencing factors. In zones I and II, increased precipitation (including cloud water) and temperature rise (causing glacier, frozen soil, and snow melt) contributed to approximately 66% of the change in lake area; in zone III, changes in precipitation contributed to approximately 87% of the lake changes. Increased atmospheric circulation of water vapor caused by warming of the ocean surface appears to be the main driving factor of these changes; this is supported by future projection scenarios. From 2006 to 2098, temperature and precipitation will increase by 4.0–7.8 °C and 1.07 to 1.29 mm per day, respectively, under both the RCP4.5 and RCP8.5 scenarios. Notably, although the climate appears to have become more optimum for lakes in CEA at the interdecadal timescale, short timescale climatic events such as lake expansion will bring more extreme climate events, such as extreme high-temperature heat waves, which should be considered as a potential threat to lake ecology in the future.