Lakes, especially the inland lakes, are sensitive to global climate change, which are the indicator of environmental variation. The area of lakes can reflect local climate change information. Thus, the rapid and accurate monitor of the dynamic change of the lake area is of great significance to analyze regional ecological environment. Based on MODIS data, this study used ESTARFM to simulate the Landsat data which are unavailable after 2000, and utilized two types of water index assisted by DEM data to analyze the dynamic area change of Siling Co Lake in Tibet from 1976 to 2014. Then, we analyzed the reasons of lake area change and its respond to climate change using the meteorological data acquired by six adjacent meteorological stations from 1976 to 2014. Conclusions can be made according to the results as the following statements. (1) The Landsat-like data acquired by ESTARFM was consistent to the real Landsat data in water information extraction, whose determination coefficient can reach a value of greater than 0.93. So, the fused data can be applied to extract the information of lakes. (2) Siling Co kept expanding from 1976 to 2014, the area of which increased approximately 711.652 km2, which is 42.36% larger. The average annual growth was about 18.728 km2, and the largest annual increase was up to 55.954 km2. The whole process of lake area change can be divided into three stages: the smooth change, the rapid change, and the smooth change again. The northern region changed most obviously, extending northward for about 22.812 km2. From 2003 to 2005, the southern region was integrated with Ya Gencuo Lake, and then they expanded together. (3) The snow-ice melting water supply caused by global warming might be the main reason for lake spread, and the decrease of wind speed was the secondary factor. However, the amount of precipitation and sunshine duration were poorly related to the lake area change.