Ischemic heart disease, as one of the major causes of morbidity worldwide, there is no effective therapy for preventing myocardial ischemia-reperfusion injury (MIRI). Baicalin, a flavonoid glycoside extracted from the Scutellaria baicalensis Georgi, yet its effects in MIRI remain unclear. In the study, pretreatment with Baicalin (100 mg/kg, i.p.) markedly alleviated I/R-induced cardiac dysfunction, as shown by reduced serum lactate dehydrogenase (LDH), creatine kinase (CK), and myocardial infarction. Baicalin also improved cardiomyocyte survival by increasing Bcl-2 and decreasing Bax and caspase-3/9 levels. In addition, Baicalin suppressed oxidative stress by reducing malondialdehyde (MDA) while elevating glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, Baicalin inhibited the STING, NLRP3, cleaved caspase-1, IL-18, and IL-1β expression in vivo and in vitro. Crucially, amidobenzimidazole (ABZI), a STING agonist, reversed the cardioprotective effects of Baicalin. Collectively, these findings demonstrated that Baicalin exerted cardioprotective effects by attenuating apoptosis and oxidative stress through suppression of STING/NLRP3 activation.