Vibrio parahaemolyticus is a common pathogen in aquatic products, such as shellfishes. Laboratory-based simulated studies demonstrated that V. parahaemolyticus can tolerate high hydrostatic pressure (HHP) up to 20 MPa. However, the molecular mechanisms of high-pressure adaptation remain unclear. Herein, we analyzed the physiological changes and transcriptomic responses of V. parahaemolyticus ATCC 17802 under HHP conditions to determine the possible survival mechanisms.