Dihydroquercetin (DHQ), a dihydroxyflavone, possesses potent antioxidant properties and is proposed to be useful in the prevention and treatment of cardiovascular disease. In this study, we aimed to investigate whether DHQ has protective effects against MIRI and to elucidate the mechanism of attenuation of oxidative stress-and ERS-induced apoptosis via the PI3K/Akt pathway. Isolated rat hearts and H9c2 cardiomyocytes were treated with or without DHQ, and then subjected to I/R and H/R, respectively. Our results showed that DHQ pretreatment markedly alleviated cardiac dysfunction, scavenged free radicals, reduced lipid peroxidation, and increased the activity of antioxidant enzymes ex vivo and in vitro. The result of western blot analysis showed that DHQ inhibited the apoptotic pathway and the expression of pro-apoptotic proteins CHOP, Caspase-12, and p-JNK. In addition, DHQ delayed the onset of ERs by reducing GRP78, p-PERK, and p-eif2α expression levels and by increasing HO-1 expression and Nrf2 binding to antioxidant response elements. These cardioprotective effects of DHQ were partially counteracted by the PI3K/Akt inhibitor LY294002. The protective effects of DHQ on the inhibition of MIRI may be mediated by activating the PI3K/Akt pathway to reduce oxidative stress-and ERS-induced apoptosis.