[Objective] The vegetation dynamics and driving factors of change in the Upper White Nile River region in the 21st century were determied in order to provide scientific guidance for the formulation and adjustment of production activities and environmental policies in the region. [Methods] The study was conducted in the Upper White Nile River region. Precipitation, temperature, and population data were analyzed by trend analysis, partial correlation analysis, and the residual trend method to determine the spatial differences in vegetation (NDVI) changes and their dominant factors in the region from 2000 to 2020. [Results] The average NDVI in the Upper White Nile River region increased at a rate of 0.105/10 a. Temperature change had a stronger impact on NDVI than precipitation. Overall, human activities had a negative impact on vegetation, but this negative impact gradually weakened over time. Shrubland was the most vulnerable of the five land cover types under the background of climate change and human activity changes (with small positive impacts and large negative impacts). Human activities mainly dominated vegetation changes in 15.01% of the land area within the watershed, while climate change dominated 84.99% of the land area. [Conclusion] Although vegetation in the basin showed an overall increasing trend, vegetation degradation had occurred in some areas, especially due to urban expansion and disturbance of farmland cultivation that have caused damage to vegetation. Local vegetation monitoring and management should be done effectively, so as to increase food production and tourism income.