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BackgroundThe use of percutaneous coronary intervention (PCI) in patients with ST‐segment elevation myocardial infarction (STEMI) is associated with a mortality rate of 5%–7%. It is clear that there is an urgent need to develop new drugs that can effectively prevent cardiac reperfusion injury. ATP‐sensitive K+ (KATP) channel openers (KCOs) can be classified as such drugs.ResultsKCOs prevent irreversible ischemia and reperfusion injury of the heart. KATP channel opening promotes inhibition of apoptosis, necroptosis, pyroptosis, and stimulation of autophagy. KCOs prevent the development of cardiac adverse remodeling and improve cardiac contractility in reperfusion. KCOs exhibit antiarrhythmic properties and prevent the appearance of the no‐reflow phenomenon in animals with coronary artery occlusion and reperfusion. Diabetes mellitus and a cholesterol‐enriched diet abolish the cardioprotective effect of KCOs. Nicorandil, a KCO, attenuates major adverse cardiovascular event and the no‐reflow phenomenon, reduces infarct size, and decreases the incidence of ventricular arrhythmias in patients with acute myocardial infarction.ConclusionThe cardioprotective effect of KCOs is mediated by the opening of mitochondrial KATP (mitoKATP) and sarcolemmal KATP (sarcKATP) channels, triggered free radicals' production, and kinase activation.