To explore the spatio-temporal variation of drought characteristics in the Loess Plateau from 2001 to 2020 and its influencing factors, MODIS enhanced vegetation index (EVI) and land surface temperature (LST) data was used to establish the temperature vegetation dryness index (TVDI) model. The driving factors of TVDI in the Loess Plateau from 2001 to 2020 were analyzed by using Geodetector Model. The results showed that from 2001 to 2020, the spatial distribution of TVDI in the Loess Plateau had a strong spatial heterogeneity, and the drought increased gradually from west to east. The average TVDI of the Loess Plateau for the past 20 years was 0.522, indicating a light drought on the whole. According to the variation trend of TVDI, more than 64% of the regions showed a drying trend, and there was an obvious regional differentiation. The drought situation in Inner Mongolia, northern Ningxia and parts of Shanxi was mostly intensifying, while the areas of alleviating drought were concentrated, mainly distributed in central Shaanxi, southern Ningxia and northern Gansu. The annual change of TVDI of all land use types showed a rising trend in varying degrees, and the annual average TVDI of each land use type was significantly different, in order from large to small as follows: unused land (0.571), grassland (0.554), cultivated land (0.503), forest land (0.473) and construction land (0.462). The spatial differentiation of TVDI in the Loess Plateau was mainly affected by three factors: elevation, soil type and vegetation type, whose q values were all exceeding 0.3, which were the main driving factors of drought in the Loess Plateau. Under the interaction of multiple factors, the combination of elevation and SIF had the strongest influence on the occurrence of drought in the Loess Plateau, with q value reaching 0.709.