To feed a rapidly growing population of 250 million, the Indus river basin in South Asia is one of the most intensively cultivated regions on Earth, highly water stressed and lacking energy security. Yet, most studies advising sustainable development policy have lacked multi-sectoral and cross-country perspectives. Here we show how the Indus countries could lower costs for development and reduce soil pollution and water stress, by cooperating on water resources and electricity and food production. According to this analysis, Indus basin countries need to ramp up investments to 10 billion USD/year to mitigate water scarcity issues and ensure improved access to resources by 2050. These costs could shrink to 2 billion USD/year, with economic gains for all, if countries pursued more collaborative policies. Downstream regions would benefit the most, with reduced food and energy costs and better water access, while upstream regions would benefit from new energy investments. Using integrated water-energy-land analysis, this study quantifies the potential benefits for novel avenues to sustainable development arising from greater international cooperation.