Abstract Methyl-3-O-methyl gallate (M3OMG) is a rare natural product that showed promising in vitro antioxidant activities. In this study, the protective role of synthetic M3OMG against sodium fluoride (NaF)-induced oxidative stress in rat brain was evaluated. Animals were treated with either M3OMG (10 and 20 mg/kg i.p.), vitamin C (10 mg/ kg i.p.) as the standard antioxidant or the vehicle (5 % dimethyl sulfoxide; 1 ml/kg) for 1 week. Oxidative stress was induced in the brain by adding 600 ppm NaF in the drinking water for 7 days. At the end of the treatment period, the levels of thiobarbituric acid reactive substances (TBARS), reduced glutathione and the activities of antioxidant enzymes (superoxide dismutase and catalase) were evaluated in brain homogenates. M3OMG treatment mitigated the NaF-induced oxidative stress through normalization of the level of TBARS, reduced levels of glutathione and by the restoration of the diminished antioxidant enzyme activities. In conclusion, M3OMG could have a potential for treating neurotoxicity induced by fluoride or related environmental pollutants.