To explore the role of the external counterpulsation (ECP) myocardial injury by controlling NRF2-mediated ferroptosis and oxidative stress damage in acute myocardial infarction.Twenty acute myocardial infarction (AMI) participants hospitalized from January 2021 to January 2022 were enrolled. In addition, 20 healthy individuals who had a physical examination at our hospital served as normal controls. Before the AMI patients were given ECP therapy, the blood samples were collected and echocardiography was performed as the data of AMI cohort. Then, the blood samples were collected and echocardiography was performed following the ECP therapy as the data of AMI + ECP cohort. The heart function was assessed by echocardiography test.Our findings demonstrated that ECP could reduce heart damage in patients with AMI. In the current study, we found that ECP could reduce heart damage in patients with AMI through increasing the LV-EF% and enhancing LVEDV and LVESV, and the difference was statistically significant (P < 0.05). ECP could reduce the levels of oxidative stress and ferroptosis markers in blood samples of AMI patients, which was through the upregulation of NRF2 and HO-1 expression, and the difference was statistically significant (P < 0.05). Taken together, all data implied that ECP was able to attenuate myocardial injury by regulating NRF2-mediated ferroptosis and oxidative stress in AMI patients, and the difference was statistically significant (P < 0.05).Our findings in this research are that cardiac ECP is able to attenuate myocardial injury by regulating NRF2-mediated ferroptosis and oxidative stress injury in AMI patients. This certainly gives the possibility of a clinically effective treatment for AMI patients, although further clinical trials need to be validated.Copyright © 2022 ShiXiang Wang et al.