The Lancang-Mekong River basin (LMRB) is facing blooming water resources infrastructure development, long-term transboundary conflicts and trade-offs between economic goals and ecosystem services provision. Yet, most studies optimizing the pathway towards sustainable infrastructure operation have lacked multi-sectoral and cross-country perspectives. Here, we quantify how and to what extent transboundary cooperation generate economic and environmental co-benefits by jointly using a coupled simulation-optimization approach and cooperative game theoretical analysis. We find that cooperation outweighs non- or partial cooperation modes to promote economic benefits by 5 to 27%, and to minimize the losses in fishery and sediment transport from 14% and 33% to 8% and 10%, respectively. Full cooperation becomes more stable alongside infrastructure expansion, climate change, and the degree of satisfying hydrological needs for river ecosystems. These findings underscore the importance of full cooperation for sustaining socio-environmental systems and suggest the needs of benefit reallocation mechanism and designed flow management for stabilizing basin-level full cooperation in the LMRB.