Anhui is one of the agricultural provinces in China. Its food security is directly influenced by the dynamics of the local ecosystems, which can be reflected through the change in vegetation net primary productivity (NPP). This study used MOD17A3 NPP data, meteorological data, and land use type data to investigate the spatio-temporal changes to vegetation NPP and its driving factors in Anhui Province from 2000 to 2015. The data was analyzed using bias analysis, coefficient of variation, trend analysis, and correlation analysis. The results showed that 1) Between 2000 and 2015, the average annual NPP for Anhui Province was 476.6 gC/m², ranging from 396.6 to 531.8 gC/m², and vegetation NPP had a strong spatial variability in Anhui Province, where it was higher in the south and lower in the northern part of the Province. 2) The average NPP varied for different land cover where forest land had the largest NPP at 535.5 gC/m². The amplitude of the NPP annual change also varied for different land cover, with the largest values being recorded for forest and grassland. 3) Vegetation NPP changes were driven by many environmental factors, such as climate change and human activities, but rainfall played the most important role. However, the large increases in human activities and urbanization have meant that they have gradually become the main forces driving NPP change.