In this study, the different powers (100−500 W) of high intensity ultrasound (HIU) were configured to investigate the mechanism of action on the tropomyosin (TM) structure, immunoglobulin G (IgG) binding capacity and digestive properties in oyster. The α-helix content of the HIU-treated TM decreased from 75.3% (control) to 41.8% (500 W) with the conversion of α-helix to random coil in TM molecules. The tertiary structure was changed with the decrease of particle size (from 165.5 to 85.6 nm) and the variety in aggregation state. Remarkably, the IgG binding capacity of TM decreased resulting from the higher power HIU treatment (300−500 W). After gastrointestinal digestion, the binding capacity of TM to IgG decreased to 1.31 with 500 W treatment, while the digestibility significantly increased. Overall, the present study suggested that the HIU-induced structural changes contributed to improving in vitro digestibility and reducing IgG binding capacity. This study contributes significant potential in terms of oyster allergen reduction.