Glaesserella parasuis (G. parasuis) is an important pathogen, which can cause systemic inflammatory response in pigs and bring huge economic losses to the global swine industry. G. parasuis can induce a strong inflammatory response in the lungs under environmental changes and certain stress conditions. However, the underlying mechanism of this adverse response has not been thoroughly studied. In this study we demonstrated that G. parasuis serotype 5 strain (GPS5-SQ) has the potential to induce pyroptosis in 3D4/21 cells. GPS5-SQ could degrade the expression of Cav-1. Knockdown or overexpression of Cav-1 promoted or reduced the occurrence of pyroptosis, respectively. These results suggested that Cav-1 is involved in pyroptosis induced by GPS5-SQ in 3D4/21 cells. In addition, overexpression of Cav-1 suppressed the activation of NLRP3 inflammasome by inhibiting ASC oligomerization, resulted in reducing pyroptosis. In general, we found that GPS5-SQ infection could promote pyroptosis by degrading the expression of Cav-1. The results of the study revealed the new mechanism of inflammation induced by GPS5-SQ in 3D4/21 cells.