<p>Water, energy, food, and ecosystems are interconnected systems and highly vulnerable to climate change. Building resilience across these systems requires an integrated approach that enhances synergy and mitigates tradeoffs. This study quantitatively examines how an integrated management approach to the Water-Energy-Food-Ecosystems (WEFE) nexus can enhance resource optimization and climate adaptation in Cameroon. Using national-level data (2000–2021), we construct a simultaneous equation model (SEM) with structural equations, and employ the 2SLS estimator with instrumental variables (IV) to identify leverage points and governance mechanisms that promote resilience and sustainability across WEFE sectors. The results indicate that energy consumption drives water demand (+ 0.49%) with a negative effect on food production (-1.52%) and ecosystem health (1.97%), potentially undermining global SDG 2 for security. Greenhouse gas emissions increase system vulnerability to climate change, while renewable energy consumption and institutions for environmental sustainability create cross-sectoral benefits in the nexus. These findings underscore the need for integrated policies that address the nexus as a coupled system, prioritizing climate-smart agriculture powered by renewable energy sources beyond hydropower. There is also a need for institutional reforms to break cycles of resource depletion and create resilience in water, energy, food, and ecosystems.</p>