Resveratrol is able to protect myocardial cells from ischemia/reperfusion‑induced injury. However, the mechanism has yet to be fully elucidated. In the present study, it is reported that resveratrol has a critical role in the control of Ca2+ overload, which is the primary underlying cause of ischemia/reperfusion injury. Hypoxia/reoxygenation (H/R) treatment decreased the cell viability and increased the apoptosis of H9c2 cells, whereas the caspase‑3 and intracellular Ca2+ levels were greatly elevated compared with the control group. Treatment of H9c2 cells with resveratrol (5, 15 and 30 µM) reduced caspase‑3 expression and cardiomyocyte apoptosis in a dose‑dependent manner, and the intracellular Ca2+ overload was also significantly decreased. Furthermore, Frizzled‑2 and Wnt5a belong to the non‑canonical Wnt/Ca2+ pathway, which have been demonstrated to be responsible for Ca2+ overload, and were thus detected in the present study. The results indicated that both the mRNA and protein expression levels of Frizzled‑2 and Wnt5a in H/R‑induced H9c2 cells were markedly increased compared with the levels found in normal cells, and treatment with resveratrol (5, 15 and 30 µM) significantly reduced the expression of Frizzled‑2 and Wnt5a compared with the H/R group. The results indicated that resveratrol protected myocardial cells from H/R injury by inhibiting the Ca2+ overload through suppression of the Wnt5a/Frizzled‑2 pathway.