Abstract: Tarim River is the longest inland river in China, which irrigates nearly one-third of Xinjiang's land in the last century. The previous unreasonable exploitation and utilization have posed a great threat to the Tarim River, particularly with the economic development and global climate change in recent years. The ecological environment of the Tarim River basin has been improved significantly, after a series of comprehensive ecological control measures, such as ecological water transfer in 2000. However, a serious challenge still remains on the sustainability of ecological restoration in the mainstream of the Tarim River under water transport projects. This study aims to clarify the dynamic change characteristics of vegetation cover in the mainstream of the Tarim River, in order to accelerate the process of vegetation protection and restoration. MODIS data was also collected from 2001 to 2021. Trend analysis and coefficient of variation were used to determine the development trend and stability of vegetation. The influence of driving factors on vegetation coverage was investigated by correlation analysis and geographical detector. The results showed that a relatively stable rising trend was found in the vegetation coverage of the mainstream of Tarim River, particularly with an annual growth rate of 2.84%. The changing trend was outstanding in seasonal fluctuations. The vegetation coverage was as high as 28.56% in summer, especially in August, but the lowest in April. There were obvious regional differences in the vegetation coverage, with the descending order of the upstream, midstream, and downstream. In 2021, the vegetation coverage in the upstream was 1.91 times as much as that in the midstream, and 3.34 times as much as that in the downstream in August. Vegetation coverage increased in 66.5% of Tarim River, most of which (49.0%) increased significantly. The combined effect of natural factors and human activities was the main reason for the rapid increase and spatial difference of vegetation coverage in the mainstream, among which the human activities posed the more direct impact on vegetation coverage. The geographical detector showed that the influence of each driving factor on the vegetation cover was ranked in descending order as follows: Land use (0.69), GDP (0.41), population density (0.37), DEM (0.30), rainfall (0.28), soil type (0.22), temperature (0.16), slope (0.04), slope aspect (0.01). The impact of human factors on the vegetation cover was mainly reflected in the change in land use type. Climatic factors (such as rainfall and temperature) presented a low correlation with the vegetation cover. The spatial distribution characteristics of vegetation cover were attributed to the interaction of multiple influencing factors. Future human activities can be more closely related to the change of vegetation cover and ecological environment evolution in the mainstream, with the influence of population growth, social and economic development. This finding can also provide the scientific basis to further understand the characteristics and driving factors of vegetation cover in the mainstream of Tarim River, particularly for the local ecological environment protection.