The human activity intensity is a comprehensive indicator that objectively reflects the impact of different human activities on the terrestrial surface and the extent of its effects. The scientific assessment for the human activity intensity has a pivotal role in coordinating regional ecological protection with human activities on the Qinghai-Tibet Plateau. However, the scale and intensity of human activities and its variation patterns on the Qinghai-Tibet Plateau are not yet clear. Therefore, there is an urgent need for quantitative study on the human activity intensity. Based on the multi-period land use survey data and the algorithm of human activity intensity of land surface, this study measured and analyzed the human activity intensity and its spatio-temporal variation characteristics on the Qinghai-Tibet Plateau in 1984, 1997, 2008, and 2018. Subsequently, the driving factors affecting the spatial variation of human activity intensity were detected using the Geographical detector model. This article obtains three conclusions:(1) the overall human activity intensity was generally at a low level on the Qinghai-Tibet Plateau from 1984 to 2018. The human activity intensity has experienced a slight decline from 1.44% in 1984 to 1.37% in 2008, while sharply rose to a high point and peaked to 1.70% in 2018. (2) The regions with the highest intensity of human activity included the Three River Basin in Tibet (Yarlung Zangbo River, Lhasa River, and Nyanchu River) and the Yellow River-Huangshui River Valley region in Qinghai, and a strip-like distribution area of relatively high intensity of human activity was being formed along the Rikaze-Lhasa-Nagqu-Yushu-Guoluo-Xining, while these regions were the lowest in the Alpine-gorge region of Sichuan and Tibet, the Northern Tibetan-Southern Qinghai Plateau, and the Pamir Mountains. (3) The geographical detection results showed that the main factors influencing the spatial differentiation of human activity intensity were population density, road density, economic scales, relief degree of land surface, urbanization rate, the proportion of primary industries, and regional development orientation, and the factors' explanatory after the interaction was significantly higher than that of single, showing the interaction types of nonlinear-enhance and bi-variable enhance. The conclusions of this study can provide a scientific support and basic reference material for government decisions on the construction of ecological security barrier and spatial governance of territorial space on the Qinghai-Tibet Plateau.