An ecosystem has been much more fragile against global warming in southwest China in recent years. Rapid and accurate monitoring of vegetation growth can greatly contribute to clarifying the response mechanism of vegetation growth to the driving factors. Therefore, it is very necessary to explore the spatiotemporal variation in the vegetation net primary productivity (NPP) under climate change and human activities. In this study, a systematic investigation was made to determine the spatiotemporal variation of vegetation NPP, and the effects of climate change and human activities on the regional and landform unit scales from 2000 to 2020. The moderate-resolution imaging spectroradiometer (MODIS) NPP was selected to combine with in situ meteorological data, population density, night-time light, and land use type datasets. Multiple mathematical models were also utilized, such as Theil-Sen Median trend, variance inflation factor, multivariate regression, residual and partial correlation analysis. Results showed that 1) there was an increasing fluctuation in the overall, predicted, and residual vegetation NPP over the past 21 years from 2000 to 2020, whereas, the Tibetan Plateau presented a relatively decrease trend. Among them, the vegetation NPP, predicted vegetation NPP, and residual vegetation NPP in the Sichuan Basin exhibited the most significant increasing trend, with a magnitude of 7.14, 3.72, and 3.44 g/(m2·a), respectively. 2) The impact of climate change on the vegetation NPP was higher than that of human activities during the study period. The areas with extremely significant and significant increases accounted for 45.18% and 18.55% of the study area, respectively, under the climate change and human activities. By contrast, the areas with extremely significant and significant increases in the predicted vegetation NPP and residual vegetation NPP in the Sichuan Basin accounted for the highest proportion in all landform units, with a magnitude of 69.42% and 50.75%, respectively. The vegetation NPP variation was dominated by the changes of temperature-like factors at the regional and landform unit scales. Specifically, the relative humidity and atmospheric pressure showed inhibitory effects on vegetation growth in southwest China. Correspondingly, the conversion of cultivated land to urban land can be an important reason for the decline of vegetation NPP, whereas, the conversion of non-cultivated land to the cultivated land and the non-forest land to forest land can be another important reason for the increase of vegetation NPP during the study period. There was an insignificant correlation of vegetation NPP with the population density and night-time light at the regional scale. Sichuan Basin exhibited the highest correlation of the vegetation NPP with population density and night-time light in all landform units at the landform unit scale. It infers that the vegetation growth in the Sichuan Basin was more associated with human activities than the rest landform units. The finding can provide a strong theoretical basis for the regional monitoring of the vegetation growth, quality assessment of the ecological environment, and benefit evaluation of forestry ecological engineering [ABSTRACT FROM AUTHOR]