Abstract: To explore effective approaches for preventing and controlling Aeromonas hydrophila infection in Alosa sapidissima. The pathogenic strain YML1 was first isolated from diseased fish and confirmed as an A. hydrophila resistant to β-lactam and tetracycline antibiotics. Antimicrobial susceptibility tests revealed that the water extract of Terminalia chebula and methyl gallate produced inhibition zone diameters of (21.00±0.75) and (24.00±1.50) mm, respectively, indicating high sensitivity. The minimum inhibitory concentration (MIC) were 5.00 mg/mL for T. chebula and 0.16 mg/mL for methyl gallate, while the minimum bactericidal concentration (MBC) was 40.00 mg/mL and 5.00 mg/mL respectively, demonstrating favorable in vitro antibacterial activity. Further investigation was conducted on the effects of dietary supplementation with T. chebula and methyl gallate on immune and antioxidant functions of A. sapidissima following challenge with A. hydrophila. The results showed that both treatments significantly improved survival rate, with T. chebula exhibiting more pronounced effects. Methyl gallate demonstrated potential as an immunostimulant, synergistically upregulating immune-related genes (lyz, tap2a, psmb9a) and antioxidant genes (gss, nrf1, cat), while simultaneously activating the complement system (C3, C4), lysozyme (LZM), and antioxidant enzyme activities (SOD, GSH-Px), thereby establishing a multi-level defense network. T. chebula enhanced basal immunity and pathogen recognition capacity of A. sapidissima through a multi-pathway, progressive mode by concurrently upregulating antioxidant genes (gss, cat), innate immune genes (lyz, tlr3), and antigen processing genes (tap2a), and significantly boosting their corresponding enzyme activities (T-SOD, GSH-Px, LZM, C3, C4). This approach effectively established robust defenses while avoiding excessive stress. In conclusion, both T. chebula and methyl gallate can effectively alleviate the stress and damage caused by A. hydrophila infection by modulating the immune-biochemical indicators and related gene expression in A. sapidissima, showing promise as potential feedadditives for bacterial disease prevention in this species.