Thorough understanding of the evolution processes and drivers behind the formation of and changes in land use and land cover (LULC) is essential for maintaining the balance between humans and fragile nature in arid regions. This quantitative driving analysis provides in-depth insight into the driving mechanisms behind the formation of and changes in LULC through a case study of the Shiyang River Basin in Northwest China. Based on land use, meteorological, topographic, and socioeconomic data from 2000 to 2018 (2000, 2005, 2010, 2015, and 2018), this study employed land use transfer matrices and the GeoDetector model to explore the evolution and driving forces behind the formation of and variations in the LULC patterns. The results demonstrated that anthropic factors mainly drove the spatial distributions of cropland and settlement. The spatial distributions of the forest, grassland, and bare land were determined by the mutual influence of natural and anthropic factors. The LULC patterns exhibited consequential variations throughout the study period. Through the occupation of the surrounding cropland and grassland, urbanization expanded rapidly. The ecological environment had been improved, but there were still considerable areas of degraded land, characterized by the grassland degradation downstream and the forest degradation upstream. Geographical differentiation was the primary driver for the transformation of bare land to grassland. The main driving forces behind urban expansion and forest loss were socioeconomic development and geographical differentiation. The degree of a certain LULC change varied among different levels of its driving factor. This research can provide scientific advice for administrators and policymakers to formulate scientific, rational, and targeted land use planning and policies in the future to achieve the sustainable development of endorheic river basins.