Lakes in the Qaidam Basin play a critical role in maintaining the fragile ecological environment. Moreover, the salt lakes in this region are important mineral resource. Since the beginning of the 21st century, lake area in this basin has changed drastically due to the driving of climate change and human activities. For further understanding lake evolution in this basin, lakes larger than 1 km² between 1976 and 2015 are derived from Landsat data. The results show that lake area in the basin has experienced four evolution stages, i.e. extension in 1976-1990, shrinkage in 1990-2000, extension in 2000-2010, and shrinkage in 2010-2015. The largest lake area is appeared in 2010. In terms of climatic and hydrological factors, the precipitation and runoff are the dominant factors for lake area variations. The change of lake area is most closely related to the precipitation and runoff in the first 3 years. Since 2000, both climate change and human activities such as water consumption in the catchment, blocking rivers and lakes connection around the lake, brine mining utilization, constructions of solar ponds have significant influence on the spatial pattern and size of the central lakes of the basin. A new lake was formed at Kushui River and south of Lake Dabuxun, the areas of Lakes Ya and Tuanjie were significantly expanded,the East and West Lake Taijinar shrank and dried, and the Lake Yiliping expanded from a playa to the largest lake in the Qaidam Basin in 2010. In view of the negative influence of the large scale exploitation of saline lakes, this paper puts forward some suggestions for the rational development of saline lake resources.