Hepatitis C virus (HCV) infection remains a significant concern for pediatric oncology patients who require multiple blood transfusions. Although direct-acting antiviral (DAA) therapies have revolutionized HCV treatment, recurrence after initial treatment can occur. We report two pediatric oncology patients who experienced HCV relapse after standard DAA regimens but responded successfully to retreatment with sofosbuvir/velpatasvir. Patient 1, a 14-year-old with acute leukemia, was diagnosed with HCV genotype 1. Despite initial successful treatment with ledipasvir/sofosbuvir, HCV RNA reappeared within 12 weeks of completing the therapy. The patient was subsequently treated with sofosbuvir/velpatasvir, resulting in sustained virologic response (SVR) at 12 and 24 weeks. Patient 2, a 5-year-old with osteosarcoma, was diagnosed with HCV genotype 3. After experiencing a relapse following treatment with sofosbuvir/daclatasvir, the patient was successfully retreated with sofosbuvir/velpatasvir, achieving undetectable HCV RNA levels at follow-up. These cases underscore the importance of early detection and vigilant follow-up in pediatric oncology patients with HCV, as well as the potential for successful retreatment with pangenotypic DAA regimens like sofosbuvir/velpatasvir. Given the evolving nature of pediatric HCV treatment, further research is crucial to optimizing treatment strategies for this vulnerable population.