Neuroblastoma (NB) is the most prevalent extracranial solid tumor in children, accounting for 8–10% of pediatric malignancies. Despite intensive multimodal therapy, prognosis for high-risk NB remains poor, necessitating targeted, less toxic therapeutic interventions. The receptor tyrosine kinase RET is overexpressed in high-risk NB. Higher RET expression correlates with poor clinical outcomes, marking it as a compelling therapeutic target. We previously demonstrated that RET knockdown results in significant cell proliferation defects. Recently we developed a novel inhibitory anti-RET mouse monoclonal antibody that enhances ADCC activity against RET-positive cells and potently inhibits proliferation across multiple human and murine NB cell lines in vitro. In vivo, treatment with our anti-RET antibody achieved complete remission without recurrence in an immunocompetent murine NB model (χ2=12.0, p=0.0025, n=4) and significantly suppressed tumor growth in human NB xenografts (χ2=7.5, p=0.0062, n=4). Critically, no adverse effects were observed in treated subjects. Furthermore, the antibody exhibited synergistic antitumor activity when combined with standard-of-care chemotherapy or ALK inhibitors in NB cell models. Our novel inhibitory anti-RET antibody demonstrates robust efficacy as both a monotherapy and a synergistic agent. These findings demonstrate that targeting RET could provide a potent, specific, and well-tolerated adjunct to current treatment regimens for high-risk NB.