Background: The aim of this study was to investigate the optimal route of administration of diltiazem in emergency PCI and to provide the best clinical treatment for ASTEMI patients. Material/Methods: A total of 90 patients with ASTEMI treated in our hospital from January 2015 to January 2016 were selected. Prior to thrombus aspiration, a thrombus aspiration catheter was used to perform diltiazem injection at the distal end of the infarct-related artery (IRA). We chose the acute ST-elevation myocardial infarction (ASTEMI) patients treated with direct PCI to compare different administration routes of diltiazem. The occurrence of major adverse cardiac events (MACEs) was closely observed during hospitalization and was obtained through out-patient visits or telephone follow-ups over the next 6 months. Results: Intracoronary infusion of diltiazem at the distal end of the culprit vessel, compared to conventional coronary mouth and intravenous injection, was significantly improved in thrombolysis in myocardial infarction (TIMI) frame count immediately after PCI stent implantation, ST-segment drop rate after 90 min, and left ventricular ejection fraction (LVEF) after 1 week. Furthermore, the peak value of high-sensitivity cardiac troponin I (hs-cT-nI), a marker for myocardial injury, was the lowest. White blood cell count, neutrophil count, mean platelet volume (MPV), and high-sensitivity C-reactive protein (hs-CRP) were significantly lower than with the other 2 administration routes, and there was no effect on intracoronary pressure or heart rate. Conclusions: Patients with ASTEMI who underwent emergency PCI treatment had good clinical outcomes using intracoronary diltiazem at the distal end of the culprit vessel.