A systematic understanding of the spatio-temporal changes and driving factors in the Qinghai-Tibet Plateau holds significant scientific reference value for the future of ecological sustainable development. This paper utilizes MODIS normalized difference vegetation index (NDVI) and meteorological data to investigate the spatio-temporal changes and driving factors of vegetation coverage in the Qinghai-Tibet Plateau from 2001 to 2020. Methods employed include the dimidiate pixel model, trend analysis, partial correlation analysis, and residual analysis. The results demonstrate a generally fluctuating upward trend in vegetation coverage across the Tibetan Plateau over the past two decades, with spatial expansion occurring from northwest to southeast. Vegetation coverage exhibits a positive correlation with climate factors. Approximately 60.7% of the area showed a positive correlation between vegetation fractional cover (FVC) and precipitation, with 8.66% of the area demonstrating extremely significant (p < 0.05) and significant (p < 0.01) positive correlation. Human activities, on the whole, have contributed to the enhancement of vegetation cover in the Qinghai-Tibet Plateau. The areas where human activities have positively impacted vegetation cover are primarily situated in north-central Qinghai and north of Ngari, while areas experiencing degradation include certain grassland regions in central-eastern Yushu, Nagqu, and Lhasa.