Tetrahydrocurcumin (THC) is an essential metabolite of curcumin, a major active component of the Curcuma species, which have been used traditionally for the treatment of cardiovascular diseases. The PI3K/AKT/mTOR signaling pathways serve a vital role during myocardial ischemia-reperfusion (MI/R) injury. The aim of the present study was to investigate the cardioprotective potential and mechanism of THC. In the in vivo study, an animal model of MI/R was induced by coronary occlusion. Results indicated that THC (50 mg/kg/day) protected the rat hearts from MI/R-induced heart failure by increasing ejection fraction (EF) and fractional shortening (FS) and decreasing left ventricular end systolic diameter (LVESD) and left ventricular end systolic volume (LVESV). THC also reduced myocardial infarct size and apoptosis. Furthermore, H9c2 cells were incubated with THC (20 μM) to explore its potential effect following exposure to hypoxia and reoxygenation (H/R). THC post-treatment significantly augmented cell viability and prevented lactate dehydrogenase (LDH) release after H/R exposure. THC effectively improved antioxidant activity by increasing SOD and CAT activities and decreasing MDA level. THC also enhanced mitochondrial membrane potential, inhibited apoptotic cell death, diminished the Bax/Bcl-2 ratio and cleaved caspase-3 level relative to the H/R model. In addition, THC effectively decreased Beclin1 expression and LC3 II/LC3 I ratio, but increased p62 expression, compared with the H/R model group, and decreased the formation of H/R-induced autophagosomes and autolysosomes. Furthermore, THC promoted the phosphorylation of PI3K/AKT/mTOR and induced the expression of hypoxia-inducible factor 1α (HIF-1α) after H/R. However, these effects on H9c2 cells were notably abolished by the PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. In conclusion, THC effectively inhibited H/R-induced autophagy and apoptosis via, at least partially, activating the PI3K/AKT/mTOR pathways. THC might have the potential to be further developed into a potential candidate for the treatment of MI/R injury.Copyright © 2021 Elsevier B.V. All rights reserved.