<p>Effective iron chelation is crucial for preventing morbidity and mortality in transfusion-dependent beta-thalassemia major. While oral chelation is the preferred mode of administration, heavily iron-overloaded patients often require combination therapy. Although desferoxamine and deferiprone are commonly recommended, a combination of two oral chelators—deferasirox and deferiprone, offers a more convenient alternative. This study evaluates the efficacy and safety of combination oral chelation in pediatric patients with severe iron overload. Children with transfusion-dependent beta-thalassemia major and persistently high serum ferritin levels (&gt; 2500&#xa0;µg/dL) for more than six months despite maximum-dose deferasirox (40&#xa0;mg/kg/day) were initiated on combination chelation with deferiprone. Serum ferritin levels were monitored at six-month intervals to assess treatment efficacy. Among 130 regularly followed patients, 27 met the criteria for combination chelation. A significant reduction in serum ferritin levels was observed, decreasing from 4277 ± 1885&#xa0;µg/dL at baseline to 3242 ± 1110&#xa0;µg/dL at six months (<i>p</i> = 0.003) and further to 2985 ± 1116&#xa0;µg/dL at twelve months (<i>p</i> = 0.018). No significant adverse effects were noted during the study period. Combination chelation with deferasirox and deferiprone is an effective and well-tolerated strategy for managing severe iron overload in children with beta-thalassemia major. This approach provides a practical alternative to injectable therapies and may improve adherence and treatment outcomes. </p>