[Objective] The mechanism of human activities affecting vegetation cover change in the Yarlung Zangbo River, Nyangqu River and Lhasa River (referred as “YNL rivers”) area of Xizang Autonomous Region was analyzed in order to provide an important theoretical basis and scientific guidance for the implementation of integrated protection and restoration projects of mountain, water, forest, farmland, lake, grass, sand, and ice in the area. [Methods] Normalized vegetation index (NDVI), land use data, ecological engineering data, and meteorological data from 2000 to 2020 were used with GIS technology, residual analysis, slope trend analysis, and the M-K test to determine the influence mechanism of human activities on temporal and spatial changes of vegetation cover in YNL rivers area. [Results] ① From 2000 to 2020, NDVI of vegetation in the study area showed an overall increasing trend, but showed a significant spatial difference. The increased area of NDVI was mainly concentrated on both sides of the river valley. ② From 2000 to 2020, the positive impact of human activities on NDVI was mainly concentrated in the valley areas of the YNL rivers, while the negative impact was mainly located in Lhasa and its surrounding areas, the distribution was less, and the positive influences was dominant. ③ Different land use types had different degrees of influence on vegetation cover change. Grassland and scrub ecosystems contributed the most to NDVI changes, reaching 92.8% in total. The urban and forest ecosystem areas increased sharply, and the increase in area of the urban ecosystem was mainly transferred from farmland and grassland ecosystems, while the forest and scrub ecosystems were mainly transferred from grassland and desert ecosystems. ④ Ecologically engineered forest was one of the main reasons for the increase in NDVI in the study area. The area change of ecologically engineered forest was positively correlated with the rate of change of NDVI and the residual change rate. The ecologically engineered forest can better explain the residual change rate. [Conclusion] Human activity is an important contributing factor to vegetation cover change in YNL rivers area of Xizang, and appropriate ecological engineering plays an important role in vegetation restoration.