Although triggered arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are often caused by increased levels of circulating catecholamines, the mechanistic link between β-adrenergic receptor (AR) stimulation and the subcellular/molecular arrhythmogenic trigger(s) is unclear. Here, we systematically investigated the subcellular and molecular consequences of β-AR stimulation in the promotion of catecholamine-induced cardiac arrhythmias. Using mouse models of cardiac calsequestrin-associated CPVT, we demonstrate that a subpopulation of Na⁺ channels, mainly the neuronal Na⁺ channels (nNa_v), colocalize with ryanodine receptor 2 (RyR2) and Na⁺/Ca²⁺ exchanger (NCX) and are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na⁺ entry via nNa_v in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA)-mediated SR Ca²⁺ refill is both an essential and a necessary factor for arrhythmogenesis. Furthermore, we show that augmentation of Na⁺ entry involves β-AR–mediated activation of CAMKII, subsequently leading to nNa_v augmentation. Importantly, selective pharmacological inhibition as well as silencing of Na_v1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo. Taken together, these data suggest that the arrhythmogenic alteration in Na⁺/Ca²⁺ handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na⁺ influx through nNa_v. Therefore, selective inhibition of these channels and of Na_v1.6 in particular can serve as a potential antiarrhythmic therapy.