The purpose of this study was to screen new drugs that can inhibit the pathogenesis of Aeromonas hydrophila and eliminate infections caused by A. hydrophila contaminated aquatic products. The results showed that tea polyphenols had no role on bacterial growth at concentrations lower than 128 μg/mL， but tea polyphenols could inhibit the hemolytic activity of aerolysin at concentrations ranging from 1-8 μg/mL. The results of thermal shift and heptamer formation assays showed that tea polyphenols could inhibit the formation of functional heptamer by directly binding to aerolysin and results in loss of activity. Cell viability assays showed that tea polyphenols of 4 μg/mL and 8 μg/mL could provide a significant protection to A549 cells from aerolysin mediated cell injury. Moreover， experimental therapeutics found that tea polyphenols at a dosage of 50 mg/kg could increase the survival rate of channel catfish infected with A. hydrophila to 60%. The above experiments showed that tea polyphenols directly bind to aerolysin and inhibit the activity of aerolysin by reducing the formation of functional heptamer， and tea polyphenols can significantly reduce the pathogenicity of A. hydrophila both in vitro and in vivo. This study suggests that tea polyphenols can be used as an alternative or adjuvant therapy to antibiotics for the treatment of A. hydrophila-related infections.