The Qinghai–Tibet Plateau (QTP) is a sensor of global climate change and regional human activities, and drought monitoring will help to achieve its ecological protection and sustainable development. In order to effectively control the geospatial scale effect, we divided the study area into eight geomorphological sub-regions, and calculated the Temperature-Vegetation Drought Index (TVDI) of each geomorphological sub-region based on MODIS Normalized Difference Vegetation Index (NDVI) and Land Surface Temperature (LST) data, and synthesized the TVDI of the whole region. We employed partial and multiple correlation analyses to identify the relationship between TVDI and temperature and precipitation. The random forest model was further used to study the driving mechanism of TVDI in each geomorphological division. The results of the study were as follows: (1) From 2000 to 2019, the QTP showed a drought trend, with the most significant drought trend in the central region. The spatial pattern of TVDI changes of QTP was consistent with the gradient changes of precipitation and temperature, both showing a gradual trend from southeast to northwest. (2) There was a risk of drought in the four seasons of the QTP, and the seasonal variation of TVDI was significant, which was characterized by being relatively dry in spring and summer and relatively humid in autumn and winter. (3) Drought in the QTP was mainly driven by natural factors, supplemented by human factors. The driving effect of temperature and precipitation factors on TVDI was stable and significant, which mainly determined the spatial distribution and variation of TVDI of the QTP. Geomorphological factors led to regional intensification and local differentiation effects of drought, especially in high mountains, flat slopes, sunny slopes and other places, which had a more significant impact on TVDI. Human activities had local point-like and linear impacts, and grass-land and cultivated land that were closely related to the relatively high impacts on TVDI of human grazing and farming activities. In view of the spatial-temporal patterns of change in TVDI in the study area, it is important to strengthen the monitoring and early warning of changes in natural factors, optimize the spatial distribution of human activities, and scientifically promote ecological protection and restoration.