To explore the antidepressant effects of oyster hydrolysates, a zebrafish model of chronic unpredictable mild stress was applied in this study. Different doses of oyster hydrolysates were used to treat the zebrafish model, which were the low concentration, medium concentration, and high concentration. The zebrafish fish behavior and body mass index were measured, and then the zebrafish peripheral cortisol contents and brain cytokine expression levels were measured by enzyme-linked immunoassay. The results showed that after 5 weeks treatment of chronic unpredictable mild stress, zebrafish showed obvious depression-like behavior, and oyster hydrolysates effectively improved zebrafish depression-like behavior, and effectively improved zebrafish weight loss after stress. At the same time,oyster hydrolysates reduced the level of cortisol in zebrafish and reduced the expression of TNF-α in the brain. The results of this study also showed that oyster hydrolysates improved chronic unpredictable mild stress-induced depression-like behavior by regulating the level of stress hormones and inhibiting the expression of inflammatory cytokines induced by chronic unpredictable mild stress. This study aims to explore the neuroprotective effects of oyster hydrolysates deeply, and provide a theoretical basis for the further development of its active ingredients.