Quantifying the contributions of human activities and climatic factors to vegetation cover change is critical for sustainable ecosystem and water resources management in arid and semiarid regions. In this study, the temporal–spatial variations of normalized difference vegetation index (NDVI) in the middle reaches of the Heihe River Basin (a typical arid endorheic basin in China) from 2000 to 2015 were detected, and a formal analytic framework was used to quantify the roles of climatic factors and human activities in driving vegetation cover change. The results showed that the study area has undergone evident overall greening with significant increases in NDVI in both oasis and desert areas. The fractional oasis area increased significantly from 22.93% to 27.69%, and the desert area decreased. The overall greening was mainly due to increases of fractional oasis area and NDVI in desert area with contributions of 50.50% and 42.08%, respectively. The increase in regional NDVI was mainly driven by gross domestic product (GDP) and precipitation with contributions of 40.2% and 40.3%, respectively, and the watertable played a secondary role in the NDVI increase with a contribution of less than 20%. This study indicated that human activities (i.e., oasis expansion) in the oasis areas and precipitation in the desert areas played decisive roles in regional NDVI changes. Coordination between expanding oases and maintaining the stability of oasis ecosystems should be reached. This study provides important references that policy makers and stakeholders can use to rationally manage ecosystem restoration and socioeconomic development and prevent land degradation in endorheic basins.