Background No-reflow phenomenon (NRP) remains a challenge in ST-elevation myocardial infarction (STEMI) patients. We determined the efficacy and safety of early intracoronary administration of nicorandil as an adjunct to primary percutaneous coronary intervention (pPCI) in STEMI patients to reduce the risk of NRP. Materials and methods In this single-center case-control prospective study, 100 STEMI patients who underwent pPCI had thrombectomy performed using a suction catheter, and tirofiban (10 mg/kg) was injected distal to the vascular lesion. All patients were divided into two groups. Group A was a treatment group (nicorandil, n=50) and group B was a control group (placebo, n=50). The primary endpoint was the composite endpoint of in-hospital cardiovascular mortality or unscheduled re-hospitalization due to deterioration of congestive heart failure that was assessed with the help of brain natriuretic peptide (BNP), left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction at six months following pPCI. The secondary endpoints were thrombolysis in myocardial infarction (TIMI) flow grade, TIMI myocardial perfusion grade (TMPG), the incidence of reperfusion arrhythmias like ventricular tachycardia and ventricular fibrillation, and ST segment elevation resolution (STR) on ECG following pPCI. Results The in-hospital cardiovascular mortality and re-hospitalization rates were 2% and 6% in the nicorandil group, whereas it was 6% and 14% in the control group. On the 180 th day of admission, the nicorandil group had significantly lower values of brain natriuretic peptide (348.45±112.32 pg/ml vs. 541.11±152.68 pg/ml, p=0.021) and left ventricular end-diastolic diameter (54.12±3.56 mm vs. 60.62±4.98 mm, p=0.011) than the control group. Nicorandil group had a significantly higher number of patients who attained TIMI 3 (p=0.022), TMPG 3 (p=0.034), and STR (p=0.008) than the control group. Ventricular arrhythmia was significantly lower in the nicorandil group than in the control group at 24 hours following pPCI (p=0.012). Conclusion Early intracoronary administration of nicorandil during pPCI may decrease the occurrence of NRP, in-hospital cardiovascular mortality, and re-hospitalization rates, as well as improve coronary blood flow and reduce reperfusion arrhythmia in STEMI patients.