Abstract Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during β‐adrenergic stimulation. Current treatment strategies include β‐blockade, flecainide, and ICD implementation – none of which is fully effective, and each with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in‐silico mutagenesis to construct a CPVT model and then used a computational modeling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na+ channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, β‐blockade, and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side effects and proarrhythmic potential plaguing CPVT pharmacologic management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na channel and benefit may be gained from an alternative multi‐drug regimen. This article is protected by copyright. All rights reserved