Aeromonas veronii, a prevalent Gram-negative bacterium in aquaculture, poses significant health risks to economically important freshwater fish species such as largemouth bass (Micropterus salmoides). This study investigates the role of pyroptosis, a highly inflammatory programmed cell death, in the immune response of largemouth bass to A. veronii infection. We characterised key pyroptosis-associated proteins, MsGSDMEa and MsGSDMEb, which harbour two conserved Gasdermin domains and are crucial in mediating pyroptosis. Following A. veronii infection, largemouth bass exhibited a robust upregulation of inflammatory cytokines (IL-1β, IL-8, TNF-α) and increased lactate dehydrogenase (LDH) activity in serum, indicating extensive cellular damage and inflammation. Quantitative real-time PCR analysis revealed a significant upregulation of pyroptosis-related genes, including NLRP3, ASC, and caspases (Caspase-1/-3/-7), in both spleen tissue and GF-1 cell line post-infection. Western blot analysis confirmed the cleavage of GSDME, a critical step in pyroptosis execution. These findings underscore the role of pyroptosis in the immune response of largemouth bass to A. veronii infection and suggest that modulating pyroptosis could be a potential strategy for disease management in freshwater fish species.