Land desertification profoundly affects economic and social development, thus necessitating a collective response. Regional land control planning needs to assess the land sensitivity to desertification across different regions. In this study, we selected 12 factors from soil, vegetation, climate, and terrain aspects to calculate and evaluate Xinjiang’s land sensitivity to desertification, from 2001 to 2020, and analyzed its trends and drivers. The results indicated that the region is highly (22.93%) to extremely sensitive (34.63%) to desertification. Of these, deserts, Gobi lands, oasis–desert transitional zones, and the downstream of rivers are highly and extremely sensitive areas. Mountainous areas, oases, and along rivers are non- and mildly sensitive areas. Over the past two decades, most areas have experienced stability (45.07%) and a slight improvement of desertification (26.18%), while the Junggar Basin and Central Taklamakan Desert have seen slight and severe intensification trends, respectively. Climate-related indicators, such as surface temperature and potential evapotranspiration (PET), were identified as the most important drivers of changes in land sensitivity to desertification. Having an integrated water resource allocation and establishing the long-term monitoring of land sensitivity to desertification would have positive implications for desertification control.