<p>The water-food-ecosystem nexus (WFE nexus) forms the foundation for achieving sustainable development. Managing ecosystem services (ESs) from this perspective is crucial for maintaining and enhancing ecosystem sustainability. However, synchronously mitigating trade-offs and supply-demand conflicts among ESs poses a significant challenge for sustainable ecosystem management. This study proposes a spatial management zoning framework integrating information on ESs trade-offs and supply-demand relationships from the perspective of the WFE nexus. This framework aims to precisely distinguish regional differences in ESs trade-off characteristics and supply-demand risk levels. We applied this framework to China’s Loess Plateau (LP) in China, where the simultaneous safeguarding of water, food, and ecological security has become a major challenge for local sustainable development. Based on analyzing ESs trade-offs and supply-demand matching relationships, our framework divided the LP into ten management zones. Each of these zones faces similar ecological issues internally, while different zones confront distinct ecological problems. Consequently, we propose targeted management strategies for each zone based on their unique ecological issues. Our framework deepens the research on the WFE nexus and provides a new perspective for simultaneously resolving ESs trade-offs and supply-demand conflicts.</p>