[Objective] The spatio-temporal evolution law of vegetation changes in the Lancang River basin was analyzed, in order to clarify the driving factors, and provide a scientific basis for the ecological protection and management of the basin. [Methods] The normalized difference vegetation index (NDVI) in conjunction with Theil-Sen trend analysis and the Mann-Kendall test were employed to systematically examine vegetation changes from 2000—2023. Furthermore, optimal parameter Geodetector was used to explore the combined effects of natural factors and human activities on spatial vegetation heterogeneity. [Results] During 2000—2023, the Lancang River basin exhibited a notable trend of vegetation improvement. In approximately 74.61% of the region, the NDVI values increased, with particularly marked recovery in low-altitude areas such as Yunnan Province. However, in northern and high-altitude regions of the basin, vegetation showed a declining trend, accounting for 25.39% of the area. The spatial distribution revealed a pattern of ‘higher in the south, lower in the north’. Elevation, land use type, and temperature were identified as the dominant factors influencing vegetation spatial variation, each explaining more than 50% of the variance. Moreover, the interaction among these factors exhibited greater explanatory power than any single factor, jointly shaping the vegetation distribution patterns across different areas of the basin. Additionally, the NDVI improvement trend significantly declined with increasing elevation, indicating that vegetation recovery and growth were severely constrained by climatic conditions at higher altitudes. [Conclusion] Strengthening ecological conservation and restoration efforts in high-altitude regions, along with implementing adaptive management strategies, will be essential for formulating more effective policies to mitigate the ecological impacts of climate change and human activities on the basin.