During the past several decades, the carbon budget in the dryland ecosystem has experienced great variation under the joint impact of climate change and anthropogenic interference. How the net ecosystem productivity (NEP) responds to climate change and human interference in the Qilian Mountains (QLM), Northwest China, remains unclear. To fill these gaps, we first estimated the NEP in the QLM and then quantified the independent and interactive influences of natural environment factors, climatic factors, and human activity intensity on the NEP change from 2000 to 2020 by linking the Geodetector and structural equation models. The NEP of the QLM showed a significant increase during the recent 20 years, and 78.93% of the QLM experienced a significant increase in NEP; while only 4.83% of the area in the QLM experienced a decreasing trend, which is dominantly located on the southeast edge, surrounding the Qinghai Lake, and the midland of the QLM. The area percentage of the carbon sink region increased from 47% in 2000 to 62% in 2020. The natural environment factors (e.g., altitude and soil type) and climate factors (e.g., temperature and precipitation) were the dominant factors that determine the spatial distribution of NEP. Compared with a single factor, the interaction of pairs of factors enhanced the influence strength on NEP. The natural environment factors indirectly affected NEP change through influencing human activities intensity and climatic factors. Human activities intensity played a medium indirectly negative effect on NEP, while climatic factors exerted strong direct and indirect positive influences on NEP. The contributions of human activity intensity, climatic factors, and natural environment on NEP change in the QLM were 33.5%, 62.3%, and 38.3%, respectively. Overall, warming and wetting shifts in meteorological conditions offset the negative impact of human activities on NEP in the QLM, and the QLM has acted as a growing carbon sink in the past 20 years.