Water, energy, food, and ecosystems (WEFE) are interconnected, comprising a coherent system (nexus) dominated by complexity and modulated by climatic and socio-economic drivers. Resource constraints, and their interconnectedness could hamper economic development, including optimal trade, market and policy solutions. Moreover, policy objectives tend to be developed with little consideration to multiple sectors, and policy implementation may change nexus characteristics, in turn affecting actor behaviour and policy formulation. NEXOGENESIS will develop and validate: (a) a coherent cross-sectoral policy-making framework at different scales addressing climate and socio-economic change, as well as stakeholder behaviour and transboundary (diplomacy) issues, developed for and validated by stakeholders, policy makers, and academics; (b) a Self-Learning Nexus Assessment Engine (SLNAE) exploiting reinforcement learning, and supporting streamlining water-related policies into the WEFE nexus; (c) a WEFE Nexus Footprint, accompanying the SLNAE. NEXOGENESIS will apply its approach to four European and one case study in southern Africa. Through the case studies, strong stakeholder engagement and validation of output, NEXOGENESIS will improve policies and policy making processes to enhance cooperation and help the EU achieve targets related to the Water Framework Directive, the greener CAP, Green Deal ambitions, as well as ambitions on water diplomacy. NEXOGENESIS outcomes, both during and after the project, will have a major impact on advancing nexus understanding and governance, resulting in a more innovative and more competitive European Union regarding nexus policy-making, backed up by state-of-the-art evidence. NEXOGENESIS will continue to drive impact after the end of the funding period through dedicated outscaling and exploitation objectives to maximise future impacts and will bring project results to extended group of users via an innovative stakeholder engagement process.