The relationship between vegetation cover and environmental evolution is currently a major research component of global change ecology. In the context of global warming and sustainable development, researches on vegetation dynamic and its driving factors is emerging as a research focus worldwide. Vegetation dynamics is a complex and long process, and it is influenced by many factors such as climatic change, land-use change, ecological engineering, and urbanization in different regions. Taking Ordos City as an example, this study investigated the temporal and spatial variation of vegetation coverage from 2000 to 2018, explored the impact of climate and human activities on vegetation change and ecological environment, identified areas affected by human activities, and distinguished positive and negative impacts. The remote sensing data, meteorological data, land use data, and mining data were analyzed by using the linear regression model, correlation analysis, and human impact model based on coefficient of variation. It was found that: (1) From 2000 to 2018, the mean of NDVI showed an upward trend of fluctuation, rising from 0.23 to 0.35. The vegetation coverage of the whole city showed a trend of transformation from low and medium coverage to medium and high coverage. (2) The variation coefficient of NDVI of vegetation from 2000 to 2018 ranged from 0.005 to 4.36, indicating the vegetation stability was weak. The regions with high coefficients of variation showed the most intense fluctuation of vegetation change, while none of the correlations between NDVI values and climatic factors (precipitation and evapotranspiration) reached the significant level. (3) The anthropogenic coefficient of variation ranged from -0.25 to 1.50, with the western part of the study area being strongly disturbed by human activities, while the eastern part was relatively less disturbed by human activities. (4) The positive impacts area of human activities are mainly concentrated in the eastern part of the study area, accounting for 54.00% of the total land area, which is closely related to ecological restoration and management in recent years.(5) The negative impact area of human activities is mainly distributed in the Kubuqi Desert and the northwest Otoki Banner, which is one of the areas with increasing mining and is largely affected by mineral development. The areas with a greater degree of negative disturbance from human activities are located in the windproof sand barrier area and the priority area of biodiversity, which have important ecological functions. Therefore, it is necessary to strengthen the conservation of biodiversity and the regulation of human activities in the western region, as well as to coordinate the relationship between economic development and environmental protection, and further contribute to the consistent improvement of regional ecological quality. The research results provided scientific support for implementing ecological restoration, optimizing the spatial development pattern of national territory and strengthening the ecological security barrier in northern China.