As the “Third Pole”, the Qinghai-Tibet Plateau is threatened by environmental changes. Ecosystem vulnerability refers to the sensitivity and resilience of ecosystems to external disturbances. However, there is a lack of relevant studies on the driving factors of ecosystem vulnerability. Therefore, based on spatial principal components analysis and geographic detectors methods, this paper evaluates the ecosystem vulnerability and its driving factors on the Qinghai-Tibet Plateau from the years 2005 to 2015. The results were as follows: (1) The ecosystem vulnerability index (EVI) of the Qinghai-Tibet Plateau is mainly heavy and extreme, showing a gradually increasing trend from southeast to northwest. (2) The spatial heterogeneity of the EVI is significant in the southeast and northwest, but not in the southwest and central parts. (3) Analysis of influencing factors shows that environmental factors have more significant effects on EVI than socioeconomic variables, facilitating the proposal of adequate policy implications. More efforts should be devoted to ecological protection and restoration to prevent grassland degradation and desertification in the high-EVI areas in northwest. The government is also urged to improve the ecological compensation mechanisms and balance ecological protection and residents’ development needs in the southeast.