During the past two decades, coral reefs have experienced extensive degradation worldwide. One etiology for this global degradation is a syndrome known as coral bleaching. Mass coral bleaching events are correlated with increased sea-surface temperatures, however, the cellular mechanism underlying this phenomenon is uncertain. To determine if oxidative stress plays a mechanistic role in the process of sea-surface temperature-related coral bleaching, we examined corals along a depth transect in the Florida Keys over a single season that was characterized by unusually high sea-surface temperatures. We observed strong positive correlations between accumulation of oxidative damage products and bleaching in corals over a year of sampling. High levels of antioxidant enzymes and small heat-shock proteins were negatively correlated with levels of oxidative damage products. Corals that experienced oxidative stress had higher chaperonin levels and protein turnover activity. Our results indicate that coral bleaching is tightly coupled to the antioxidant and cellular stress capacity of the symbiotic coral, supporting the mechanistic model that coral bleaching (zooxanthellae loss) may be a final strategy to defend corals from oxidative stress.