Aim To observe the inhibition effect of oxysophoridine (OSR) on myocardial cell apoptosis after acute myocardial infarction (AMI) in rats through nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) pathway. Methods Adult healthy male SD rats were divided into sham-operated group (Sham group), AMI group, OSR group, OSR＋zinc protoporphyrin (ZPP-Ⅸ) group. The left anterior descending coronary artery ligation was used to establish the AMI model in the latter three groups. OSR was intraperitoneally injected into OSR group, OSR and HO-1 inhibitor ZPP-Ⅸ were intraperitoneally injected into OSR＋ZPP-Ⅸ group. The contents of serum myocardial enzymes, apoptotic rate of cardiomyocyte, expressions of apoptotic gene, Nrf2 and HO-1 in myocardium were detected. Results The serum contents of lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase isoenzyme MB (CK-MB), myocardial cell apoptotic rate, and the expressions of Bcl-2 associated X protein (Bax), Cleaved-caspase-3, Nrf2 and HO-1 in myocardium in AMI group were significantly higher than those in Sham group, and the expression of B-cell lymphoma-2 (Bcl-2) in myocardium was significantly lower than that in Sham group. The serum contents of LDH, CK, CK-MB, myocardial cell apoptotic rate, and the expressions of Bax and Cleaved-caspase-3 in myocardium in OSR group were significantly lower than those of AMI group, and the expressions of Bcl-2, Nrf2 and HO-1 in myocardium were significantly higher than those in AMI group. The serum contents of LDH, CK, CK-MB, myocardial cell apoptotic rate, and the expressions of Bax and Cleaved-caspase-3 in myocardium in OSR＋ZPP-Ⅸ group were significantly higher than those in OSR group, and the expression of Bcl-2 in myocardium was significantly lower than that in OSR group. Conclusion OSR can inhibit myocardial cell apoptosis after AMI by activating Nrf2/HO-1 pathway in rats.