The Water–Energy–Food (WEF) nexus is an important conceptualization that demonstrates the interdependency of the fundamental resources and how climate change disrupts the global and regional agri-food systems systemically. Climate change enhances water, energy, and food pressures, which cause cascading trade-offs that jeopardize food security, water availability, and energy reliability especially in climatic sensitive areas like the Sub-Saharan Africa (SSA) and South Asia. Traditional monoculture-based agriculture, which is highly reliant on water, energy, and external resources, is becoming exposed to higher extremes of temperature, changes in precipitation, and extreme weather, which intensifies the shortage of resources and socio-economic imbalance. Neglected underutilized crops (NUCs), drought- and heat-tolerant, low-input, and rich in nutrients, can be used as a feasible solution to improve the resilience of the WEF nexus. Resource intensity can be decreased, food production can be stabilized during climatic stress, nutritional results can be enhanced, and local livelihood and food sovereignty can be promoted by their incorporation into diversified agri-food systems. This chapter analyzes climate change as a systemic cause of WEF vulnerabilities, interactions and trade-offs between water, energy and food systems and identifies NUCs as a strategic course of adaptation. The policy implications are based on integrated governance, investment in climate-resilient infrastructure, the encouragement of the low-resource system of cropping, and alignment with Sustainable Development Goals (SDGs) to attain sustainable, resilient, and inclusive WEF systems. Using NUCs as a component of a nexus-driven system provides an avenue to creating adaptive, nutritionally sensitive, and climate-resilient food systems that can help solve the challenges in SSA and South Asia and other vulnerable locations of the future.