AbstractSudden cardiac death (SCD) remains a major cause of global mortality. In addition to modern interventions, botanical folk medicines have long been used to treat cardiovascular disease, although the efficacy and underlying mechanisms are often unresolved. Aloperine, a bioactive quinolizidine alkaloid isolated from Sophora alopecuroides plants, exhibits antioxidant, anti‐inflammatory, antitumor, and vasorelaxant properties, but possible antiarrhythmic effects of aloperine in SCD are unclear. Here, we examined whether aloperine protects against ischemia and reperfusion injury‐associated lethal ventricular arrhythmia and sudden cardiac death. Rats were divided into sham, control, and aloperine groups, and reperfusion‐provoked ventricular arrhythmogenesis, cardiac damage markers, and signaling pathways quantified following left main coronary artery ischemia and reperfusion. In vitro studies of effects of aloperine on hERG and Kv4.3 cardiac voltage‐gated potassium (Kv) channels were performed using two‐electrode voltage clamp analysis of cloned channels expressed in Xenopus laevis oocytes. Aloperine pretreatment (10 mg/kg) did not affect baseline cardiac electrical stability; yet, it reduced ventricular arrhythmogenesis and susceptibility to SCD (mortality rate: control: 64.3%; aloperine: 0%) induced by reperfusion injury. Aloperine also reduced serum levels of LDH, CK‐MB, α‐HBDH, and cTnI post‐I/R, and stimulated phosphorylation of ventricular ERK1/2 and STAT‐3, which are key components of RISK and SAFE signaling pathways. Inhibition of either ERK1/2 (with U0126) or STAT‐3 (with Ag490) abolished aloperine‐induced anti‐arrhythmic effects and ERK1/2 and STAT‐3 phosphorylation. Interestingly, while aloperine (100 μM) had no effect on cloned Kv4.3 activity, aloperine (1 μM and up) negative‐shifted the voltage dependence of hERG activation by ~10 mV and increased peak hERG current by 35%. Thus, aloperine exerts striking anti‐arrhythmic effects against myocardial ischemia and reperfusion injury‐induced severe lethal ventricular arrhythmia and sudden cardiac death via the ERK1/2/STAT‐3 signaling pathway, with potential additional contribution from increased cardiac myocyte repolarization capacity via augmented hERG activity.