Lakes are sensitive indicators of anthropogenic climate change and also respond to direct human activities. Yet, long-term lake inventories and quantitative evaluation of the factors driving observed lake changes across China remain elusive. Here, for the first time, we examined multi-decadal lake area changes in China during 1960s−2015, using historical topographic maps and more than 3831 Landsat satellite images, including lakes as fine as ≥1 km2 in size. In addition, we quantified the causes of lake changes from climatic and anthropogenic factors. The total area of lakes in China has increased by 5858.06 km2 (9%) between 1960s and 2015, and with heterogeneous spatial variations. Lake area changes in the Tibetan Plateau, Xinjiang, and Northeast Plain and Mountain regions reveal significant increases of 5676.75, 1417.15, 1134.87 km2 (≥15%), respectively, but the Inner-Mongolian Plateau shows an obvious decrease of 1223.76 km2 (22%). We find that 141 new lakes have appeared predominantly in the arid western China; but 333 lakes, mainly located in the humid eastern China, have disappeared over the past five decades. We conclude that climate factors have played a dominant role in lake changes across China, coupled with noticeable anthropogenic contribution of ~35% in the Eastern Plain and Yunnan-Guizhou Plateau. This study has substantial implications to improve decision support regarding water-resource management strategies and land-use planning throughout China.