The glucagon-like peptide-1 analog liraglutide has been proved to exert cardioprotective role via activating prosurvival pathways and suppressing inflammation. The activation of NLRP3 inflammasome plays an important role in ischemic injury. The effect of liraglutide on NLRP3 inflammasome-dependent pyroptosis remains unclear. In this study, we established a double stimulation model with TNF-α and hypoxia to mimic ischemic environment and to induce NLRP3 inflammasome activation in H9c2 cardiomyoblasts. Pretreatment with 100 nM liraglutide could efficiently inhibit TNF-α and hypoxia-induced inflammasome activation, as evidenced by the decreased expression of NLRP3, caspase-1 p20 and Gasdermin D N-terminal fragment. Meanwhile, the pyroptosis was also demonstrated to be suppressed, indicated by the increased cell viability and decreased lactate dehydrogenase release in the cells. Mechanistically, liraglutide reversed the level of SIRT1 and the selective SIRT1 inhibitor EX 527 significantly abolished the anti-pyroptosis role of liraglutide. Furthermore, liraglutide diminished the levels of ROS generation and NOX4 expression, which could also be blocked by EX 527. Our results uncovered the anti-pyroptosis role of liraglutide in TNF-α and hypoxia-stimulated H9c2 cells, which was associated with SIRT1/NOX4/ROS pathway.