Objective To explore the mechanism of ferroptosis in a rat model of myocardial ischemia?reperfusion injury (MIRI), basing on the theory of heartache governing liver. Methods SD rats were divided into a blank group (n=10), sham operation group (n= 10), model group (n= 10), Conggan Zhixin recipe group(CGZX group)(n= 10), and Shexiang Baoxin Pill group (SXBX group)(n= 10) in accordance with a random number table. Except in blank and sham operation groups, all groups underwent ligation of the anterior descending coronary artery and ischemia?reperfusion to establish a myocardial ischemia?reperfusion injury model. The drug was administered by gavage at 24 h after model establishment. The gavage cycle was 14 days, and the frequency was once a day. Blood was collected from the abdominal aorta on day 16, and serum contents of creatine kinase isoenzyme (CK?MB), cardiac troponin T (cTnT), superoxide dismutase (SOD), malondialdehyde (MDA), and polyunsaturated fatty acid (PUFA) were analyzed by ELISA. The harvested heart was stained with HE to observe pathological morphology of myocardial tissue and with Prussian blue to observe iron deposition of myocardial cells. Mitochondrial morphology after ferroptosis was observed in ventricular muscle by electron microscopy. mRNA and protein expression of Nrf2 and ACSL4 in the myocardium was measured by PCR and Western Blot, respectively. Results Compared with the normal group, rats in the model group had obvious myocardial tissue and ultrastructure damage under the electron microscope, broken or loose myofilaments, swollen mitochondria in myocardial tissue, and a large amount of dark brown iron deposition in myocardial cells. The serum contents of CK?MB, cTnT, MDA, and PUFA were increased (P< 0?? 01), while the SOD content was decreased (P< 0?? 01). Moreover, mRNA and protein expression of Nrf2 and ACSL4 in the myocardium was increased significantly (P< 0?? 01). Compared with the model group, Conggan Zhixin recipe significantly improved edema and degeneration of myocardial tissue, reduced the iron deposition of myocardial cells and the degree of cell crest relaxation, significantly reduced the serum contents of MDA, PUFA, CK?MB, and cTnT (P< 0?? 01), upregulated SOD (P< 0?? 01)and Nrf2 expression in myocardial tissue, and downregulated the mRNA and protein expression of ACSL4 (P< 0?? 01). Conclusions Conggan Zhixin recipe has a myocardial protective effect on MIRI rats, which may be related to regulation of the Nrf2?ACSL4 pathway and inhibition of myocardial cell ferroptosis.