Objective This study is aimed at investigating the mechanism of α -cyperone in oxygen and glucose deprivation- (OGD-) induced myocardial injury. Methods Cardiomyocytes were exposed to OGD and then treated with α -cyperone. The cell counting kit-8 (CCK-8) assay and flow cytometry were performed to determine cell proliferation and apoptosis, respectively. The expression of inflammatory factors was monitored by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The profiles of apoptosis-related proteins, inflammatory proteins, and the Akt/FOXO3a/NF- κ B pathway were determined by western blot. The phosphorylation of Akt, FOXO3a, and NF- κ B was determined by immunofluorescence assay. The superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content were gauged by the colorimetric method, and the reactive oxygen species (ROS) content was measured. Results α -Cyperone hindered OGD-induced inflammation, oxidative stress, and apoptosis in cardiomyocytes. OGD activated the FOXO3a/NF- κ B pathway and hampered the Akt phosphorylation. α -cyperone reversed OGD-mediated FOXO3a/NF- κ B pathway activation. Treatment with MK-2206 abated the protective effect of α -cyperone against OGD-induced myocardial injury. The addition of α -cyperone to cardiomyocytes following Bay11-7082 treatment had no conspicuous effect on the viability and apoptosis. Conclusions α -Cyperone protected cardiomyocytes against OGD-induced inflammation and oxidative stress via the Akt/FOXO3a/NF- κ B axis.