The Greater Mekong Sub-region (GMS), including five Southeast Asian countries and China, has experienced a significant increase in the cultivation of opium, trafficking of heroin and methamphetamine, and consumption of these illicit drugs. In recent years, the GMS has been expanded considerably as supply, destination, and transit route for illegal drug trade’s networks to and through, particularly when China officially applied ‘Belt and Road’ strategy. This paper reviews historical aspects and current trends in drug production and trafficking in the GMS, with special emphasis on Mekong River areas where China is ‘located’ as the heart of the transition. Some evidence consistent with the ‘supply, destination, and transit route’ arguments is found through locating and mapping drug trafficking networks to connect with China. Finally, this paper calls for some initial recommendations to improve the process of bilateral and multilateral cooperation in the GMS within the scope of Belt and Road Initiative.