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Under the multiple stresses of global warming and human activities, land degradation in the Three River Source Region is becoming increasingly severe. However, the researches on large-scale land degradation monitoring models based on remote sensing are fewer and not yet mature. In this study, based on MODIS data products, five factors, including surface albedo, greenness index, heat index, topsoil grain size index, and salinity index, are introduced. These five factors are used to propose a novel large-scale land degradation remote sensing index based on the dynamic weighting method in Three River Source Region. Then the spatio-temporal evolution and driving mechanism of land degradation in the past 20 years are analyzed. The results showed that: (1) The land degradation remote sensing index model proposed in this study has good applicability, and its monitoring accuracy is 92.1%. (2) The average intensity of land degradation in the past 20 years in the Three River Source Region is 0.34, which generally belonged to the mild and moderate degradation. The Yangtze River Source Region has the most significant intensity of land degradation. (3) The gravity center of land degradation in the Three River Source Region during 2001–2020 generally shows a trend of eastward migration. (4) From 2001 to 2020, the change of land degradation intensity in the Three River Source Region was small, showing a trend of overall stability and a slight partial improvement. (5) The impacts of temperature, precipitation, and GDP density on land degradation are significantly different. From 2001 to 2020, the soil was the dominant factor determining land degradation, while the correlation between temperature and land degradation intensity in the study area was small. The results can provide relevant theoretical and technical support for land degradation management and ecological environment restoration in the Three River Source Region. [ABSTRACT FROM AUTHOR]