Background Myocardial ischemia-reperfusion injury (MI/RI) poses a significant challenge during coronary revascularization. This research investigated alterations in oxidative stress and ferroptosis, alongside the impact of nicorandil on these aspects, among patients undergoing acute ST-elevation myocardial infarction (STEMI) and receiving primary percutaneous coronary intervention (pPCI).Methods 121 patients with STEMI who were undergoing pPCI were included in the study, and we documented their thrombolysis in myocardial infarction (TIMI) blood flow grades before and after the procedure. The serum levels of creatine kinase-MB, creatinine, and N-terminal prohormone of brain natriuretic peptide (NTpro-BNP) were assessed. Additionally, we analyzed serum levels of SIRT1, HIF-1 alpha, GPX-4, FTH1, FSP1, 4-HNE, and SI before pPCI and 6 h post-pPCI. Follow-ups were conducted 12 weeks after discharge, with major adverse cardiovascular events (MACEs) documented.Results The nicorandil group showed significantly improved TIMI blood flow grades and lower CK-MB and NTpro-BNP levels at 24, 48, and 72 h after PCI. Although preoperative SIRT1, HIF-1 alpha, and ferroptosis-related indicators were similar, post-PCI, SIRT1 increased less and HIF-1 alpha increased more in the nicorandil group. The nicorandil group exhibited higher GPX4, FTH1, and FSP1 levels, and lower levels of 4-HNE and SI. While no significant differences in left ventricular function were observed, the nicorandil group had lower LVEDD at 12 weeks. Importantly, the incidence of unstable angina and heart failure was significantly lower in the nicorandil group.Conclusion Administering nicorandil perioperatively during pPCI alleviates MI/RI, preserves cardiac and renal function, and reduces unstable anginarisk at 12 weeks post-PCI. These benefits of nicorandil may be attributed to its anti-oxidative stress and anti-ferroptosis effects.