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This work explored the effects of salinity and temperature on the efficacy of purging <i>V. parahaemolyticus</i> from eastern oysters (<i>Crassostrea virginica</i>). Oysters were inoculated with a 5-strain cocktail of <i>V. parahaemolyticus</i> 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 <i>V. parahaemolyticus</i> 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 <i>Vibrio</i> at Day 7, which meets the FDA’s requirement as a post-harvest process for <i>V. parahaemolyticus</i> control. At the conditions of 10 °C and 20 ppt, a pre-chilled system could achieve a 3.54 log (MPN/g) reduction of <i>Vibrio</i> 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%.