Our results demonstrated that melatonin alleviated cardiomyocyte loss by inhibiting NLRP3 inflammasome-mediated pyroptosis by modulating the Toll-like receptor 4 (TLR4)/NF-κB signaling pathway and further clarified that melatonin may be a promising agent for MI treatment. The gene discussed is TLR4; the disease is myocardial infarction.