Land surface temperature (LST) directly affects the energy balance of terrestrial surface systems and impacts regional resources, ecosystem evolution, and ecosystem structures. Xinjiang Uygur Autonomous Region is located at the arid Northwest China and is extremely sensitive to climate change. There is an urgent need to understand the distribution patterns of LST in this area and quantitatively measure the nature and intensity of the impacts of the major driving factors from a spatial perspective, as well as elucidate the formation mechanisms. In this study, we used the MOD11C3 LST product developed on the basis of Moderate Resolution Imaging Spectroradiometer (MODIS) to conduct regression analysis and determine the spatiotemporal variation and differentiation pattern of LST in Xinjiang from 2000 to 2020. We analyzed the driving mechanisms of spatial heterogeneity of LST in Xinjiang and the six geomorphic zones (the Altay Mountains, Junggar Basin, Tianshan Mountains, Tarim Basin, Turpan-Hami (Tuha) Basin, and Pakakuna Mountain Group) using geographical detector (Geodetector) and geographically weighted regression (GWR) models. The warming rate of LST in Xinjiang during the study period was 0.24°C/10a, and the spatial distribution pattern of LST had obvious topographic imprints, with 87.20% of the warming zone located in the Gobi desert and areas with frequent human activities, and the cooling zone mainly located in the mountainous areas. The seasonal LST in Xinjiang was at a cooling rate of 0.09°C/10a in autumn, and showed a warming trend in other seasons. Digital elevation model (DEM), latitude, wind speed, precipitation, normalized difference vegetation index (NDVI), and sunshine duration in the single-factor and interactive detections were the key factors driving the LST changes. The direction and intensity of each major driving factor on the spatial variations of LST in the study area were heterogeneous. The negative feedback effect of DEM on the spatial differentiation of LST was the strongest. Lower latitudes, lower vegetation coverage, lower levels of precipitation, and longer sunshine duration increased LST. Unused land was the main heat source landscape, water body was the most important heat sink landscape, grassland and forest land were the land use and land cover (LULC) types with the most prominent heat sink effect, and there were significant differences in different geomorphic zones due to the influences of their vegetation types, climatic conditions, soil types, and human activities. The findings will help to facilitate sustainable climate change management, analyze local climate and environmental patterns, and improve land management strategies in Xinjiang and other arid areas.