The metabolism of cities is shaped not only by local characteristics but also by interactions with neighbouring cities within an interconnected regional system. Building on the Metabolism of Interconnected Cities framework, this study examines how spatial proximity and inter-city interdependence are associated with regional metabolic outcomes. It is applied in the three regions of Belgium as a case study. Spatial econometric techniques, including the Spatial Durbin Model, alongside OLS and K-means clustering, were deployed to identify structural and spatial drivers of energy use and waste generation, along with their direct and spillover effects. Results reveal significant spatial associations for both variables, with distinct regional patterns. Energy consumption is primarily explained by local factors, whereas waste generation exhibits strong spatial interdependence across cities. The findings highlight how differences in economic structure, urban form, and land-use characteristics are associated with contrasting regional metabolic outcomes and can inform policies accounting for inter-city interdependence.