Natural resources conservation is considered indispensable for a sustainable future. A thorough managerial analysis of the current and future conservation and availability to meet future demands is both necessary and challenging. As water of adequate quantity and good quality is required for a favourable condition of natural ecosystems and for agricultural production, a comprehensive analysis which would consider hydrological, environmental and agricultural dimensions is needed to properly address their interactions and potential impacts. This study presents a Water-Ecosystems-Food (WEF) nexus methodological flamework aiming at identification and mitigation of critical challenges. The framework is tested in a highly productive water basin in north Greece, the Kokkinorema River Bain, which is also characterised by intense agriculture practices. The presented methodological approach was developed in the context of a natural resources sustainability scheme adapted by the national funded AgroClim project. The selection and prioritisation of the most efficient measures, including Nature-based Solutions, would be driven by a Decision Support System (DSS) tool which will feed upon ecological, social, economic and legislative information. The proposed DSS will also incorporate future climate scenarios to evaluate and address expected future water scarcity, ecosystems degradation and reduced agricultural productivity issues. The proposed methodology for addressing nexus challenges could be transferred to any other natural resources-stressed water basin with similar characteristics.