Background: Oxidative stress may be a key risk factor for cataract and glaucoma, and many previous reports have suggested that antioxidants could be a promising treatment. Here, we investigated the effects of a novel supplement containing three food-derived antioxidants (hesperidin, crocetin, and tamarindus indica) on markers of oxidative stress in patients with these conditions. Methods: This study had a prospective, single arm design. Fifty Japanese subjects with cataract and glaucoma were recruited and asked to refrain from the use of vitamin or carotenoid supplements for 2 weeks before the study. The subjects took 4 tablets together with ample water twice a day for 8 weeks, stopped the treatment, and were then followed for an additional 8 weeks. The subjects were examined at four-week intervals, for a total of 5 examinations. We measured biological antioxidant potential (BAP) with a free radical analyzer. Clinical laboratory data, including malondialdehyde (MDA) and superoxide dismutase (SOD), were measured in venous blood samples. Clinical parameters were also recorded. The Mann-Whitney U test and Fisher’s exact test were used to determine the significance of differences between groups. Other comparisons used a one-way analysis of variance (ANOVA) followed by the Student’s t-test or Dunnett’s test.Results: BAP was significantly elevated at weeks 8, 12, and 16 (P = 0.007, P = 0.035, P = 0.015). The MDA level was significantly reduced at week 8 (P = 0.019). BAP changes were recorded by subtracting the value at week 8 from week 0. Multiple regression analysis revealed that SOD, total bilirubin and diabetes were independent contributing factors to the change in BAP (P = 0.039, P = 0.019, P = 0.013). There were no supplement-related adverse events or abnormal results in blood testing in any of the patients.Conclusion: Our study found that an 8-week oral course of antioxidant supplementation was effective in patients with a low antioxidative stress level. Dietary supplementation holds promise in the treatment of systemic oxidative stress-related diseases.Trial registration: UMIN-CTR UMIN 000032050