This work explored the effects of salinity and temperature on the efficacy of purging V. parahaemolyticus from eastern oysters (Crassostrea virginica). Oysters were inoculated with a 5-strain cocktail of V. parahaemolyticus to levels of 104 to 105 MPN (most probable number)/g and depurated in a controlled re-circulating wet-storage system with artificial seawater (ASW). Both salinity and temperature remarkably affected the efficacy for the depuration of V. parahaemolyticus from oysters during wet-storage. The wet-storage process at salinity 20 ppt at 7.5 °C or 10 °C could achieve a larger than 3 log (MPN/g) reduction of Vibrio at Day 7, which meets the FDA’s requirement as a post-harvest process for V. parahaemolyticus control. At the conditions of 10 °C and 20 ppt, a pre-chilled system could achieve a 3.54 log (MPN/g) reduction of Vibrio in oysters on Day 7. There was no significant difference in the shelf life between inoculated and untreated oysters before the depuration, with a same survival rate (stored in a 4 °C cooler for 15 days) of 93%.