Coral reefs are increasingly threatened by global climate-driven stressors and local anthropogenic pressures, both of which can impair coral physiology. However, the relative influence of these stressors on in situ coral physiological performance remains poorly understood. Understanding how environmental variability influences coral stress responses in therefore critical for improving reef health assessments and informing effective management strategies. Here, we investigated how spatial variability in trace metals and seawater environmental parameters modulates oxidative stress in the reef-building coral Pocillopora favosa across nearshore-offshore gradients in three regions of the central Red Sea that differ in anthropogenic intensity levels. To address this, we integrated measurements of seawater trace metal and nutrients concentrations, coral tissue metal bioaccumulation, and a suite of oxidative stress biomarkers, including indicators of antioxidant defense, detoxification capacity and cellular damage. Our results indicate that distance from shore, rather than apparent gradients of human activity, was the main predictor of coral biochemical responses. Nearshore colonies exhibited higher carboxylesterases activity and protein content, whereas offshore colonies displayed enhanced superoxide dismutase activity, suggesting spatially distinct strategies potentially linked to oxygen dynamics and chronic exposure to land-derived inputs. Overall, our findings highlight a mismatch between perceived anthropogenic pressure and the physiological stress responses observed in corals. This study underscores the importance of multi-metric diagnostic frameworks that integrate contaminant analyses with physiological biomarkers, enhancing the accuracy of reef health assessments and enabling the refinement of pollution thresholds in the face of accelerating environmental change.