Background <p>This study investigated the efficacy of resveratrol in reducing ventricular arrhythmia (VA) and modulating calcium handling in a heart failure (HF) model.</p> Methods <p>HF rabbits were established five weeks after coronary artery ligation. The groups included control, HF rabbits, and HF rabbits treated with intraperitoneal injections of resveratrol 2.5&#xa0;mg/kg (HF + Res group) in the last week. The electrophysiology of the left ventricle (LV) was investigated using epicardial optical mapping. The action potential duration (APD), calcium transient duration (Ca_iTD), level of fibrosis and apoptosis, and protein and mRNA levels of ion channels and calcium-handling proteins were also measured.</p> Results <p>The HF group demonstrated a reduction in LV ejection fraction, an augmentation in APD₈₀ and Ca_iTD₈₀, and an escalation in VA inducibility. The administration of resveratrol resulted in the restoration of cardiac function, a reduction in APD₈₀ and Ca_iTD₈₀, and a decrease in VA, phase singularities, and dominant frequency. In HF, the expression of ion channels such as Cav1.2, RyR, Nav1.5, Kv1.4, Kv1.5, and Kir2.1 was significantly decreased. The level of SERCA2a, a calcium pump essential for intracellular calcium regulation, was also reduced. Treatment with resveratrol effectively restored the expression of these proteins. Concurrently, HF-induced elevations in fibrosis (collagen I), apoptosis (caspase-3), and inflammation (NF-κB) were significantly attenuated by resveratrol. Proteomic profiling further revealed differential regulation of ion channel–associated proteins and enrichment of cardioprotective signaling pathways, underscoring the therapeutic potential of resveratrol in HF.</p> Conclusions <p>Resveratrol ameliorates calcium handling, reverses structural and electrical remodeling, and suppresses VA in a rabbit HF model.</p> Graphical abstract <p></p>