The protective effects of vitamins E and C against methanol-induced free radical production with its subsequent tissue injury in liver and retina of male albino rats were assessed. The rats were divided into four groups: (1) control, (2) antioxidant (Ao) control group receiving 5 mg of each vitamin, E and C, (3) daily ip-injected methanol (2 mL/kg b.wt.) group, killed after three and six doses, and (4) Ao/methanol group administered the vitamins 3 weeks prior to and along with methanol injection and killed as the latter group [Sharpe et al. Methanol Optic Neuropathy: A Histopathological Study. Neurology 1982, 32 (10), 1093–1100]. Methyl alcohol drastically altered the Ao defense system and energy status of rat liver, where highly significant depletion of glutathione levels and inhibition of superoxide dismutase activity, concurrent with significant increase in thiobarbituric acid reactive substances indicating marked elevation in lipid peroxidation. These effects were reversed when the vitamins were administered denoting their role in promoting the Ao defense system. Furthermore, they also increased the methanol-induced depletion in adenylate energy charge, phosphate potential, and ATP values. The amelioration in the energy status as a result of vitamins E and C supplementation suggests that their role as Aos is effective in relieving the impaired oxidative phosphorylation in order to increase the energy demand under physiologically stressful conditions. Histopathological and ultrastructural results of rat retina confirmed the protective effect of Ao vitamins. As compared to the methanol-intoxicated group, the protected group showed preservation of the membranous structures of the retinal cells, especially mitochondria that assumed their normal shape. This may be attributed to the inhibition of free radical production and lipid peroxidation and subsequently minimum degree of tissue damage. Amelioration of mitochondrial structure reflected the improvement of impaired oxidative phosphorylation of intoxicated animals with an approximately normal level of energy demand. This suggests that Ao vitamins may alter the retinotoxic effects of methanol by promoting the internal Ao defense system and preserving the energy status of the animal.