Biodiversity is vital to the sustainable future of human beings, yet environmental changes and anthropogenic activities cause an alarming rate of species extinction globally, threatening the conservation of biodiversity. Here, we assessed the vulnerabilities of one of the most biodiverse but also most fragile ecosystems in the world, the Yarlung Tsangpo River Basin (YTRB), to multiple ecological and social stressors. We conducted an indicator-based assessment to quantify the vulnerability of the YTRB to multiple social and ecological stressors; and evaluated the interactions among aspects of vulnerabilities by comparing their spatial patterns. Our results show that areas with the highest ecological vulnerabilities were highly clustered, and the most critical determinants for ecological vulnerability were temperature and precipitation variations. Also, increases in population density and high human footprint were the most vulnerable aspects of social vulnerability, accounting for 39 % and 31 % of the total area. Spatial patterns of social and ecological vulnerabilities were different. Areas with high ecological vulnerability were mostly observed in the west and north part of the basin; whereas high social vulnerabilities mostly along the central river and the southeast part. The selected ten variables representing social and ecological vulnerabilities were highly independent, especially the four variables relating to social vulnerability. Our results reveal significant conflicts between conservation and development because of the large areas showing high social and ecological vulnerabilities (22 % of the entire area). For the part of the YTRB belonging to the global biodiversity hotspots, also being the forested areas, the most vulnerable ecological aspect was vegetation loss, rather than climate variations. Our study provides a temporally dynamic and spatially explicit evaluation of social and ecological vulnerabilities of the YTRB, contributing to informed decision-making to sustain the biodiversity of this highly fragile ecosystem, meaningful to global biodiversity conservation.