Desertification poses a serious threat to the global ecological environment and challenges the achievement of an ecological civilization. Understanding the spatial and temporal evolution of desertification in the Mu Us Desert, a key area in northern China, is crucial for predicting regional trends and analyzing causes. This study employs quantitative methods, including remote sensing data from Landsat satellites (2000–2020), combined with multi-scale analysis and statistical models, to systematically analyze desertification trends. The analysis reveals that desertification improved significantly after 2005 due to effective human intervention and governance efforts. In particular, the eastern regions (Shaanxi Province and Inner Mongolia) showed marked improvement, while the western regions exhibited limited change. The greatest progress was seen in the reduction in high-desertification areas to moderate levels. Quantitatively, human activities contributed to a 17.3% reduction in desertification (p < 0.05), while meteorological factors were responsible for a 45.8% reduction (p < 0.05). Conversely, desertification in Ningxia worsened by 41.8% due to unsustainable land use. Additionally, spatial correlation analysis highlighted that those areas of severe desertification became more uniformly distributed over time. The key drivers influencing desertification were agricultural development, urbanization, climate warming, and vegetation coverage, with human activities playing a substantial role. Initially, agricultural factors had the strongest correlation with desertification, but over time, population growth, rising temperatures, and vegetation cover (NDVI) became more prominent. These findings offer scientific support for desertification control in the Mu Us Desert and provide methodological insights for other severely desertified regions, contributing to sustainable ecological development.