Cinnamaldehyde (CD) is one of the most important active compounds derived from Cinnamomum cassia and showed multiple biological activities. Accumulating evidence has shown that the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome significantly contributes to sterile inflammatory response and gasdermin D (GSDMD)-mediated pyroptosis in myocardial ischemia/reperfusion injury (MI/RI). Whether CD has any influence on NLRP3 inflammasome activation and pyroptosis during myocardial I/R injury remains unknown. In the present study, we investigated the cardioprotective effect of CD via establishing the MI/RI rats' model by ligating the left anterior descending coronary artery for 30 min ischemia followed by 120 min reperfusion. Sprague-Dawley rats were intragastrically administered with CD (45 and 90 mg/kg/d) or vehicle for 7 successive days before ligation of the coronary artery to evoke MI/RI. The results found that CD significantly improved cardiac diastolic function, decreased cardiac infarct size and myocardial injury enzymes, inhibited cardiomyocyte apoptosis, attenuated cardiac structure abnormality, and mitigated oxidative stress and inflammatory response. We also found that MI/RI activated the NLRP3 inflammasome as evidenced by the upregulation levels of NLRP3, pro-caspase-1, caspase-1, and ASC proteins and mRNA. Importantly, MI/RI could trigger cardiomyocyte pyroptosis by increased DNA fragmentation, membrane pore formation, and mitochondrial swelling as well as increased levels of pyroptosis-related proteins and mRNA, including GSDMD, IL-18, and IL-1β. As expected, all these deleterious alterations were reversed by CD pretreatment. Our findings demonstrated that CD showed an outstanding cardioprotective effect via inhibiting NLRP3 inflammasome activation and GSDMD-mediated cardiomyocyte pyroptosis, which has a promising application value and development prospect against myocardial I/R injury in the future.