Achieving land degradation neutrality (LDN) is considered critical to achieving sustainable development goals. However, further research and an improved large-scale desertification assessment framework are needed. We constructed a comprehensive land desertification status index (LDSI) to assess desertification and its driving mechanisms in Central Asia from 2001 to 2020. Our spatial distance models and principal component analysis were verified by combined field data. The results indicate that desertification levels in Central Asia fluctuated, decreasing from south to north and increasing from west to east. The extent of increased desertification (45.75%) and recovery (45.65%) were nearly equivalent. According to optimal parameters-based geographical detectors, climate factors are the main contributors to desertification, the most significant being reference evapotranspiration. We also found regional differences in the driving mechanisms of desertification. Based on Theil–Sen, Mann–Kendall, and Hurst tests, future desertification intensification of 9.69% is possible, with hotspots mainly in northwestern Central Asia, while 9.73% restoration may occur in other areas. The findings have relevance for achieving LDN. Policymakers should monitor the impact of global climate change and develop recovery measures based on comprehensive consideration of local climate, soil, and terrain conditions.