The Paleo-Tethys and Panthalassa are two major oceans that witnessed the end-Permian mass extinction, and they have been suggested to have distinct compositions, with the Paleo-Tethys Ocean euxinic, and the much larger Panthalassa Ocean being largely ventilated. Distinctions of these two once-connected oceans imply that interactions between them must have been restricted shortly before the end-Permian extinction. However, detailed geological processes for the disconnection between them along the eastern Paleo-Tethys Ocean due to the collision of North and South China, are still unclear. Previous geochronological studies on eclogite facies rocks in the Dabie–Sulu orogenic belt, which are the metamorphic products of the collision between North and South China, have yielded mainly Triassic metamorphic ages. Nonetheless, new Permian metamorphic ages are identified from southeastern North China, northern Dabie, and the Permo–Triassic intracontinental orogen of South China, which may collectively closely associate this major tectonic event with the end-Permian extinction. New age dating results, as well as a synthesis of recent studies on metamorphic rocks, show that the onset of the collisional orogenesis dates back to the Middle Permian (270–252 Ma). We thereby provide a new tectonic model for the major continents of East Asia, in which the initial collision between North and South China during the Middle Permian critically isolated the Paleo-Tethys Ocean from the Panthalassa Ocean, facilitating the oceanographic transition of the once fossiliferous Paleo-Tethys from a life-giving nutrient-rich ocean into a euxinic death trap, thereby serving as prelude to the end-Permian extinction.