Silymarin is a well-known potent antioxidant agent. Numerous reports highlighted that antioxidant consumption can mitigate sodium fluoride induced neuronal damage. The present study aimed to examine the ameliorative potential of silymarin on sodium fluoride-induced oxidative stress using the rat brain as model. Silymarin (10 and 20 mg/kg) and vitamin C (10 mg/kg) were intraperitoneally administrated for seven days followed by one week of sodium fluoride (600 ppm) treatment through drinking water. Antioxidant enzyme activities – superoxide dismutase and catalase – the levels of reduced glutathione and lipid peroxidation were evaluated in brain homogenates. The levels of lipid peroxidation were significantly increased in the sodium fluoride treated group (42.0 ± 2.1 nmol MDA eq/g tissue) compared to the control group (36.0 ± 1.1 nmol MDA eq/g tissue). Silymarin at 20 mg/kg showed significant a reduction in the levels of lipid peroxidation (36.0 ± 1.2 nmol MDA eq/g tissue). Treatment of rats with sodium fluoride significantly reduced the activities of the antioxidant enzymes and the levels of reduced glutathione in brain homogenates. Pre-treatment with silymarin prevented the deleterious effects of sodium fluoride intoxication in a dose dependent response. In conclusion, sodium fluoride induced oxidative stress in rat brain which can be prevented with silymarin administration.