The Lancang-Mekong River Basin is facing booming water resources infrastructure development, long-term transboundary conflicts and trade-offs between economic goals and ecosystem services provision. Optimizing the pathway towards sustainable infrastructure operation has lacked multisector-coordinated and decision behaviour-based perspectives for transboundary water systems. In this study we quantified how, and to what extent, transboundary cooperation generates economic and environmental co-benefits by jointly using a coupled simulation–optimization approach and cooperative game theoretical analysis. We found that full cooperation outweighs partial or non-cooperation modes to promote economic benefits by 3 to 21% and to minimize the losses in fishery and sediment transport from 23% and 60% to 12% and 22%, respectively. Full cooperation becomes more beneficial and stable alongside infrastructure expansion, climate change and satisfying the hydrological needs of river ecosystems. These findings underscore the importance of full cooperation for sustaining socio-environmental systems and highlight the need for a benefit reallocation mechanism and designed flow management to stabilize basin-level full cooperation in the Lancang-Mekong River Basin.