Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Purpose Mutations in desmosome gene Plakophilin-2 (PKP2) account for approximately 40% of ARVC cases and result in reduced gene expression. Our goal is to examine the feasibility and the efficacy of restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Methods Adeno-associated virus 9 (AAV9) was used to deliver a wild-type copy of PKP2 gene that is driven by a cardiac-selective promoter and expressed selectively in cardiomyocytes. Results We demonstrated that a single-dose AAV9-mediated PKP2 gene therapy effectively prevented disease onset before overt cardiomyopathy and attenuated disease progression after overt cardiomyopathy. Restoration of PKP2 expression led to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, attenuating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. Additional RNA sequencing analyses showed that durable restoration of PKP2 expression led to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusion These results indicate that a cardiac-selective AAV9-mediated PKP2 gene therapy may be a promising one-time treatment for ARVC patients with PKP2 mutations.