Safe, reliable, and equitable water access is critical for healthy livelihoods. Climate change-related water stress is challenging, and using the Water-Energy-Food-Ecosystems (WEFE) nexus is an appealing approach for sustainable management. The contribution of this paper is formulating a comprehensive framework integrating water sectors and ecosystems. The paper fills previous gaps in the literature by taking Spain’s Ebro Basin as a case study for evidence to guide science-based policies. Results deliver a framework for measuring the distribution of benefits and costs among sectors and stakeholders. Findings reveal choices that increase stream flows, enhance water security and biodiversity, and reduce climate risks.