Desertification, a current serious global environmental problem, has caused ecosystems and the environment to degrade. The total area of desertified land is about 1.72 million km2 in China, which is extensively affected by desertification. Estimating land desertification risks is the top priority for the sustainable development of arid and semi-arid lands in China. In this study, the Mediterranean Desertification and Land Use (MEDALUS) model was used to assess the sensitivity of land desertification in China. Based on multi-source remote sensing data, this study integrated natural and human factors, calculated the land desertification sensitivity index by overlaying four indicators (soil quality, vegetation quality, climate quality, and management quality), and explored the driving forces of desertification using a principal component and correlation analysis. It was found that the spatial distribution of desertification sensitivity areas in China shows a distribution pattern of gradually decreasing from northwest to southeast, and the areas with very high and high desertification sensitivities were about 620,629 km2 and 2,384,410 km2, respectively, which accounts for about 31.84% of the total area of the country. The very high and high desertification sensitivity areas were mainly concentrated in the desert region of northwest China. The principal component and correlation analysis of the sub-indicators in the MEDALUS model indicated that erosion protection, drought resistance, and land use were the main drivers of desertification in China. Furthermore, the aridity index, soil pH, plant coverage, soil texture, precipitation, soil depth, and evapotranspiration were the secondary drivers of desertification in China. Moreover, the desertification sensitivity caused by drought resistance, erosion protection, and land use was higher in the North China Plain region and Guanzhong Basin. The results of the quantitative analysis of the driving forces of desertification based on mathematical statistical methods in this study provide a reference for a comprehensive strategy to combat desertification in China and offer new ideas for the assessment of desertification sensitivity at macroscopic scales.