The Mediterranean Sea Basin (MSB) is experiencing increasing pressure on its natural resources due to climate change (CC) and demographic growth, posing challenges to water and food sustainability. In line with the United Nations Sustainable Development Goals and the Water-Energy-Food-Ecosystems (WEFE) nexus, this study projects shifts in welfare and food security under various climatic conditions. Agriculture, a sector that is highly vulnerable to climate variability, depends predominantly on rainfed croplands, which constitute 70-100% of agricultural land in most MSB countries. The remaining areas are irrigated by climate-dependent water bodies such as rivers and aquifers. A comprehensive analysis of the WEFE nexus is essential for a coherent examination of climate policy and future pathways for the economy and the natural environment. Using a dual-modeling approach, this research assesses the impacts of alternative water sources and irrigated agriculture within the MSB amidst uncertainties of CC-driven extreme events. A global computable general equilibrium (CGE) model, based on the GTAP framework, will be used to examine inter-sectoral and inter-regional impacts. In tandem, the Integrated Assessment Model (IAM) based on the RICE-99 framework quantifies the uncertainties related to future extreme climatic events. This synergistic approach provides a comprehensive assessment of CC impacts, integrating adaptation strategies for alternative water sources and irrigated agriculture, as well as mitigation strategies to reduce greenhouse gas emissions from energy production. The focus on cross-sectoral and multi-scale management of water, ecosystems, and food in the MSB was embedded into the economic models – CGE GTAP-AW and IAM RICE-MED, to analyze the impacts of CC adaptation and mitigation strategies on the WEFE nexus. The results indicate a reduced impact of CC on food production, and provide a comprehensive overview of potential adaptation and mitigation measures to reduce food security risks in the MSB. These findings are crucial for policymakers to promote sustainable water and agricultural practices in the face of a changing climate.