Background and purpose: Iron overload in the body is associated with serious and irreversible tissue damage. This study aimed to investigate the iron-chelating, antioxidant, anti-inflammatory, and hepatoprotective activities of grape seed extract (GSE) supplement as well as its safety in beta-thalassemia major (beta-TM) pediatric patients receiving deferasirox as a standard iron-chelation therapy.Materials and methods: The children were randomly allocated to either GSE group (n = 30) or control group (n = 30) to receive GSE (100 mg/day) or placebo capsules, respectively, for 4 weeks. The serum levels of iron, ferritin, total iron-binding capacity (TIBC), alanine transaminase (ALT), aspartate aminotransferase (AST), tumor ne-crosis factor alpha (TNF-alpha), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and gluta-thione (GSH) as well as superoxide dismutase (SOD) activity and hemoglobin (Hb) concentration were measured pre-and post-intervention.Results: GSE supplement significantly attenuated the serum levels of iron (p = 0.030), ferritin (p = 0.017), ALT (p = 0.000), AST (p = 0.000), TNF-alpha (p = 0.000), and hs-CRP (p = 0.001). The TIBC level (p = 0.020) signif-icantly enhanced in the GSE group compared with the placebo group. Moreover, GSE supplement remarkably improved the oxidative stress markers, MDA (p = 0.000) and GSH (p = 0.001). The changes in the SOD activity (p = 0.590) and Hb concentration (p = 0.670) were not statistically different between the groups. Conclusion: GSE supplement possesses several health beneficial influences on children with beta-TM by alleviating iron burden, oxidative stress, inflammation, and liver dysfunction.