Fractional vegetation cover (FVC) is an important indicator of regional ecological environment change, and quantitative research on the spatial and temporal distribution of FVC and the trend of change is of great significance to the monitoring, evaluation, protection, and restoration of regional ecology. This study estimates the FVC of the eastern Tibetan Plateau margin from 2000 to 2020 using the image element dichotomous model based on the Google Earth Engine platform using MODIS-NDVI images. It also investigates the temporal and spatial changes of the FVC in this region and its drivers using the Theil–Sen and Mann–Kendall trend tests, spatial autocorrelation analysis, geodetector, and machine learning approaches impact. The results of this study indicated a generally erratic rising tendency, with the Min River Basin (MRB) near the eastern tip of the Tibetan Plateau having an annual average FVC of 0.67 and an annual growth rate of 0.16%. The percentage of places with better vegetation reached 60.37%. The regional FVC showed significant positive spatial autocorrelation and was clustered. Driver analyses showed that soil type, DEM, temperature, potential evapotranspiration, and land use type were the main drivers influencing FVC on the eastern margin of the Tibetan Plateau. In addition, the random forest (RF) model outperformed the support vector machine (SVM), backpropagation neural network (BP), and long short-term memory network (LSTM) in FVC regression fitting. In summary, this study shows that the overall FVC in the eastern margin of the Tibetan Plateau is on an upward trend, and the regional ecological environment has improved significantly over the past two decades.