The human activity impact index (HAII) was calculated based on the potential NPP and the actual NPP. Seven natural factors, such as vegetation type, elevation and slope, were further selected and analyze the spatial differentiation combined with HAII, so as to reveal the influence rules of multiple factors at a more detailed seasonal scale. The results showed that the explanatory power and significance of HAII were better than that of human activities in describing the spatial differentiation of vegetation NPP in the Qinghai-Tibet Plateau. In terms of the spatial differentiation of NPP affected by multiple factors, both natural factors and man-made factors showed obvious seasonal differences. The explanatory power of human activities was the highest in summer, weakened in spring and autumn, and was mainly affected by natural factors in winter. Among them, slope, temperature, normal direct radiation and scattered radiation showed a single driving influence in spring, autumn and winter, in summer when vegetation living conditions were better, the factors appeared obvious inflection point, precipitation factor limit threshold changed with the season. In the interaction of factors, the interaction among human activities, precipitation, temperature, and vegetation types was the main driving force which affect NPP in the Qinghai-Tibet Plateau. Combining HAII and multiple natural factors, in the construction of vegetation ecological engineering on the Qinghai-Tibet Plateau, four factors (human activities, precipitation, temperature, and vegetation type) should be mainly considered, and the dominant factors were different in different seasons. In arid and rainless areas, human activities should be given priority. The study aims to provide a reference basis for regional ecosystem management in areas under different vegetation habitat conditions.