Background and Purpose Vibrio vulnificus (V. vulnificus), a gram-negative bacterium, causes serious wound infections and septicemia. Once it develops into early-phase sepsis, hyperinflammatory immune responses result in poor prognosis in patients. The present study aimed to examine the possible underlying pathogenic mechanism and explore potential agents that could protect against V. vulnificus cytotoxicity. Experimental Approach The anti-pyroptotic effects of P2X7 receptor (P2X7R) antagonists were assessed in an experimental murine V vulnificus infection. In vitro, the effects of P2X7R antagonists on V vulnificus-induced anti-phagocytosis and pyroptosis in murine macrophages were examined. Key Results Here, we report that infection of mouse macrophages with V. vulnificus triggers anti-phagocytic effects and pyroptotic inflammation via ATP-mediated purinergic P2X7R signaling. V. vulnificus promoted P2X7-dependent NF-κB p65 translocation, modulating the expression of the inflammasome sensor NLRP3, adaptor ASC, and pyroptotic protein gasdermin D (GSDMD) in mouse macrophages. V. vulnificus induced the NLRP3/caspase-1 inflammasome signaling complex expression that drives GSDMD transmembrane pore formation and secretion of IL-1β, IL-18, and MIP-2. This effect was blocked by P2X7R antagonists, indicating that the P2X7R mediates GSDMD-related pyroptotic inflammation in macrophages through the NF-κB/NLRP3/caspase-1 signaling pathway. Furthermore, blockade of P2X7R reduced V. vulnificus-colony-forming units in the spleen, immune cell infiltration into the skin and lung tissues, and serum concentrations of IL-1β, IL-18, and MIP-2 in mice. Conclusions and Implications These results indicate that P2X7R plays a vital role in mediating phagocytosis by macrophages and pyroptotic inflammation during V. vulnificus infection and provides new opportunities for therapeutic intervention in bacterial infections.