Total saponins of Aralia elata (Miq.) Seem. (TSAE) have been shown to play a significant role in cardiovascular protection, anti-tumor, liver protection, anti-oxidant stress, and anti-inflammation. However, the specific mechanisms of TSAE in myocardial ischemia-reperfusion injury (MIRI) remain largely elusive. Hearts from male Wistar rats were used to establish the isolated heart MIRI model. Using a multichannel physiological recorder, the whole course heart rate (HR), left ventricular development pressure (LVDP), and maximum rise/decrease rate of left ventricular pressure (±dp/dt ) were recorded. 2,3,5-triphenyl-2H-tetrazolium chloride staining observed the infarct area, while hematoxylin & eosin staining detected pathological changes in myocardial tissue. Creatine kinase, lactate dehydrogenase, total superoxide dismutase, and malondialdehyde concentrations were determined by enzyme-linked immunosorbent assay. Immunohistochemistry, quantitative PCR, and western blot assay were used to assess the amounts of IL-18 and IL-1β, NLR family protein (NLRP3) inflammasome- and apoptosis-related proteins, respectively. Treatment with TSAE or MCC950 (NLRP3-specific inhibitor) significantly reduced the myocardial infarction area, alleviated pathological changes in myocardial tissues, enhanced LVDP and ±dp/dt levels, prevented myocardial oxidative damage, and inhibited NLRP3 inflammasome formation. In addition, TSAE enhanced Akt and GSK3β phosphorylation, and LY29004 co-reperfusion markedly diminished the protective role of TSAE reperfusion on cardiac function, oxidative damage, and inflammatory responses. Collectively, TSAE treatment exhibited a protective effect on I/R-triggered inflammatory responses, cell necrosis, and oxidative stress injury by stimulating PI3K/Akt signaling-mediated NLRP3 inflammasome inhibition.