Abstract: Understanding the evolution of vegetation cover and its driving mechanisms are crucial for ecological security in arid inland river basins. The impacts of natural factors and human activities are particularly crucial for vegetation restoration. This study, taking the middle and lower reaches of the Heihe River Basin as study area, mainly explored the spatiotemporal variations of the Normalized Difference Vegetation Index (NDVI) from 2000 to 2022 and its driving factors by using the Mann-Kendall test, Theil-Sen Median trend analysis, and time-lag correlation analysis, and then quantified the contributions of natural factors and human activities to NDVI changes by using the multiple regression models. The results indicated that, the spatial variability of NDVI changes in the study area was significant, with slight improvement in the irrigation area in the middle reaches and the right bank in the lower reaches, accounting for 76.6%, and slight degradation in the left bank in the lower reaches, accounting for 23.4%; Climate warming and increasing runoff from the upper reaches had a positive effect on vegetation restoration, and there was a 4-month lag effect of surface and root soil moisture on NDVI; The proportion where natural factors contribute more than 65% to NDVI changes in the study area is 26.7%, and the proportion where human activities contribute more than 65% is 58%; Human activities contributed more to the NDVI changes on the right bank in the lower reaches, while natural factors contribute more to the left bank.