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Vegetation cover is important to the stability of regional ecosystems and is a focus of research on the relationship between natural and human environments. Although some studies have investigated the association between changes in vegetation cover and various influencing factors, these have shortcomings in quantifying direct and indirect effects. In this study, MOD13Q1 enhanced vegetation index (EVI) data for Anhui Province, China, were acquired between 2000 and 2020. The univariate linear regression, coefficient of variation and Hurst index methods were used to analyze spatial and temporal trends and fluctuations in the EVI between 2000 and 2020 and predict future trends. The impact of land-use change on EVI change was explored using 2000 and 2020 land-use data. Finally, a structural equation model (SEM) was used to quantify the effects of topography, annual average temperature, annual precipitation and human activity changes on EVI variation in Anhui Province. The results show that (1) from 2000 to 2020, the overall EVI in Anhui Province showed a fluctuating trend that increased at a rate of 0.0181·10a−1, and 67.1% of the study area showed a greening trend. The EVI was relatively stable in most regions, with regions of fluctuating EVI being mostly affected by urbanization. For a period after 2020, the overall EVI change will exhibit anti-sustainability and will likely decrease. (2) Among the regions of EVI increase, 72.2% had no change in land-use type, while 10.8% and 6.6% changed to farmland and woodland land uses, respectively. Among the regions where EVI decreased, 69.9% had no change in land-use type, while 13.7% changed from farmland to construction land. (3) Overall, human activity change was the main influence on EVI change, which was mainly reflected in the negative impacts of accelerated urbanization. Topography had direct and indirect effects on EVI variations in Central and Southern Anhui. Annual precipitation change had a stronger impact on EVI variation in Northern and Central Anhui than in Southern Anhui, while annual average temperature change had a small impact in the entire province. Compared with other study methods, SEM provides a new approach to quantifying the influences of vegetation cover dynamics. In addition, the results of this study have important implications for ecological environmental protection and sustainable development in Anhui Province. [ABSTRACT FROM AUTHOR]