The Xunhua Basin, a subbasin of the Longzhong Basin in an arid region of the northeastern Tibetan Plateau, hosts a thick succession of Upper Cenozoic fluvial-lacustrine sediments containing climate-sensitive freshwater mollusks, which can provide key insights into the uplift history of the Tibetan Plateau and its relationship to global climate change. In this study, we studied six genera and eleven species of freshwater mussels of the family Unionidae from the Upper Miocene Liushu Formation of the Xunhua Basin. These genera include Unio, Acuticosta, Anodonta, Cristaria, Lanceolaria and Ptychorhynchus. The fossils not only enhance our understanding of biological diversity on the Miocene Tibetan Plateau but also shed light on the biological response to Late Cenozoic orogenic uplift and environmental changes. The Unionidae family is present in modern China mainly in freshwater lakes on the middle and lower reaches of the Yangtze River Basin, i.e., in a humid subtropical monsoonal climate, and it has been extinct in northwestern China (including Qinghai Province) since the Late Miocene. This modern distribution implies that environmental conditions in the Xunhua Basin during the Late Miocene were substantially more humid than at present. Such a sharp contrast in habitat to that of the modern Xunhua Basin implies that a Late Miocene climate shift on the NE Tibetan Plateau occurred after 8.2 Ma, i.e., a climatic drying and cooling trend triggered both by regional tectonic uplift and global climate change, which significantly impacted freshwater ecosystems in the Xunhua Basin.