Aquatic animals inhabiting marine coastal environments are highly susceptible to environmental fluctuations and pollution, exemplified by widespread mass mortalities induced by marine bacteria or viruses. Enhancing antioxidant defenses presents a promising strategy to mitigate such environmental stressors. We postulated that supplementation of oysters with natural compounds such as flavonoids, exemplified by curcumin (CUR), could effectively bolster their antioxidant protection. Adult Pacific oysters were supplemented with CUR (30 μM) in seawater for 2, 4, 8, and 16 days. CUR metabolites progressively accumulated in gills, mantle, and digestive glands. Notably, oyster antioxidant response was significantly augmented, as evidenced by elevated glutathione (GSH) levels, and enhanced activities of glutathione reductase (GR), thioredoxin reductase (TrxR), and glutathione S-transferase (GST) after 4, 8, and 16 days of CUR supplementation. This response was tissue-specific, with the most pronounced increase in gills, followed by mantle, whereas digestive gland exhibited minimal response. After being supplemented with CUR for 8 days, oysters were subjected to antioxidant-disrupting agents such as N-ethylmaleimide (NEM), 1-chloro-2,4-dinitrobenzene (CDNB). Both chemicals reduced antioxidant protection in untreated animals. However, CUR supplementation prevented these redox-disrupting effects, suggesting the potential ability of CUR to counteract antioxidant stressors. The effects of 8 days of CUR supplementation were also tested against the lethal effects of the pathogens V. tapetis, V, alginolyticus, and V. anguillarum, but CUR failed to induce immunological protection. The antioxidant protection induced by CUR holds promise for application in aquaculture to bolster animal health and resilience against abiotic stressors. Further research is needed to investigate the long-term impact of CUR supplementation and its role against biotic stressors, such as bacterial and viral infections.