The Indus River Basin covers an area of around 1 million square kilometers and connects four countries: Afghanistan, China, India, and Pakistan. More than 300 million people depend to some extent on the basins water, yet a growing population, increasing food and energy demands, climate change, and shifting monsoon patterns are exerting increasing pressure. Under these pressures, a business as usual (BAU) approach is no longer sustainable, and decision makers and wider stakeholders are calling for more integrated and inclusive development pathways that are in line with achieving the UN Sustainable Development Goals. Here, we propose an integrated nexus modeling framework co-designed with regional stakeholders from the four riparian countries of the Indus River Basin and discuss challenges and opportunities for developing transformation pathways for the basins future.