Atorvastatin has protective effects against myocardial ischemia–reperfusion injuries and ischemia–reperfusion arrhythmia. This study was designed to investigate whether atorvastatin is able to protect against myocardial ischemia–reperfusion injury by enhancing the expression of Connexin 43 (Cx43) via the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and mitochondrial ATP-sensitive potassium (KATP) channels. Isolated perfused rat hearts were treated with classic ischemia postconditioning (IPOST), atorvastatin, and atorvastatin combined with inhibitor of PI3K and KATP channels, respectively, after 30 min of LAD ischemia and then subjected to reperfusion for 120 min. The QRS duration and the ischemia–reperfusion ventricular arrhythmia were assessed. The lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) levels were measured and the Cx43 expression was assessed by immunoblotting and immunohistochemistry. After 120 min of reperfusion, atorvastatin and IPOST significantly decreased the QRS duration and inhibited ventricular arrhythmia. They also decreased the levels of LDH and CK-MB. Meanwhile, atorvastatin and IPOST also significantly enhanced the Cx43 expression and the phosphorylation of Cx43. Such protective effects were abolished in the presence of the inhibitor of PI3K or the inhibitor of mitochondrial KATP channels. This study suggests that atorvastatin protected against myocardial ischemia–reperfusion injury and enhanced the expression of Cx43 by activating the PI3K/Akt pathway and mitochondrial KATP channels.