Climate change and human activities are two factors that have important effects on the carbon cycles of terrestrial ecosystems. Quantitative assessment of the relative effects of climate change and human activities on net primary productivity (NPP) of the ecosystem could significantly improve understanding of the mechanisms driving the system and help prevent desertification expansion. We used Shule River Basin as the study area. The potential NPP (PNPP) was calculated using remote sensing and meteorological data, and the difference between the PNPP and actual NPP (ANPP) during the period 2001-2015 was used to assess the effect of climate change and human activities on the NPP in the basin. The following conclusions were made:(1) the annual ANPP of the Shule River Basin increased slowly and was generally lower than that in Northwest China and the average for China. The overall productivity of vegetation in the basin was not high. The spatial distribution results showed that the annual ANPP was high in the upstream Qilian Mountains and the mid-downstream oasis region and low in the mid-downstream Gobi region. (2) The annual PNPP trend between 2001 and 2015 indicated that precipitation is the primary factor driving vegetation degradation in the Shule River Basin, but the effect of temperature change on vegetation is complex. (3) Between 2001 and 2015, vegetation degradation was caused by human activities in most areas of the basin, but the negative effect of human activities is weakening. (4) The spatial heterogeneity was detected from the relative effects of climate change and human activities on the NPP, but human activities were the main factors driving vegetation change in the Shule River Basin.