Interconnected food, energy, and water (FEW) nexus systems face many challenges to support human well-being (HWB) and maintain resilience, especially in arid and semiarid regions like New Mexico (NM), United States (US). Insufficient FEW resources, unstable economic growth due to fluctuations in prices of crude oil and natural gas, inequitable education and employment, and climate change are some of these challenges. Enhancing the resilience of such coupled socio-environmental systems depends on the efficient use of resources, improved understanding of the interlinkages across FEW system components, and adopting adaptable alternative management strategies. The goal of this study was to develop a framework that can be used to enhance the resilience of these systems. An integrated food, energy, water, well-being, and resilience (FEW-WISE) framework was developed and introduced in this study. This framework consists mainly of five steps to qualitatively and quantitatively assess FEW system relationships, identify important external drivers, integrate FEW systems using system dynamics models, develop FEW and HWB performance indices, and develop a resilience monitoring criterion using a threshold-based approach that integrates these indices. The FEW-WISE framework can be used to evaluate and predict the dynamic behavior of FEW systems in response to environmental and socioeconomic changes using resilience indicators. In conclusion, the derived resilience index can be used to inform the decision-making processes to guide the development of alternative scenario-based management strategies to enhance the resilience of ecological and socioeconomic well-being of vulnerable regions like NM.