We aim at assessing the impact of α-lipoic acid (ALA) supplementation on the oxidative stress markers, Hb-derivatives, erythrocytes' hemolysis, and liver function of β-thalassemia major (β-TM) patients. We studied 10 β-TM patients who were assessed by evaluation of serum ferritin, plasma malondialdehyde (MDA), erythrocytes' hemolysis, serum alanine transaminase (ALT) and aspartate transaminase (AST) activities, methemalbumin (Mha), oxyhemoglobin (HbO2), total bilirubin (TB), and hemoglobin (Hb) derivatives following 3 and 6 months of supplementation with 300–600 mg/day of ALA according to age. 12 healthy volunteers of the same age and sex were examined at baseline only and did not receive ALA. We detected a significant decrease in serum ferritin levels, plasma lipid peroxidation (MDA), and serum oxyhemoglobin concentrations (p<0.05) after 6 months of treatment with ALA, which suggests a reduction in iron overload and oxidative stress. This decrease in oxidative damage can account for the decrease in the percentage of erythrocytes' hemolysis (p<0.0005), liver enzyme activity of ALT and AST by (p<0.05) and (p<0.005) after 3 and 6 months of treatment with ALA, respectively, indicating liver function improvement, which was confirmed by decreasing serum TB concentration (p<0.054) after 6 months of supplementation. However, there was an insignificant effect of ALA on the levels of Hb-derivatives. Still, a 7.54% increase in total blood Hb-concentration indicates improvement of anemia after 3 months of ALA supplementation. Those results highly support the clinical usage of ALA in supplementing the treatment of β-TM patients to alleviate the severity of symptoms resulting from iron overload and oxidative stress.