Objectives The purpose of this study was to demonstrate the effect of methyl-3O-methyl gallate (M3OMG), a rare polyphenolic natural product with a potent in-vitro antioxidant effect, against sodium fluoride (NaF)-induced oxidative stress in rat erythrocytes in vivo. Methods Male Wistar rats were treated daily with either M3OMG (10 and 20 mg/ kg) obtained through synthesis, vitamin C (10 mg/kg) or vehicle intraperitoneally for 7 days. Oxidative stress was then induced by exposing animals to NaF (600 ppm) through drinking water for 7 days. At the end of intoxication period, rats were killed and erythrocytes isolated. The activity of antioxidant enzymes (catalase and superoxide dismutase) and levels of reduced glutathione and thiobarbituric acid reactive substances were measured in erythrocyte haemolysates. Results NaF intoxication resulted in a 1.9-fold increase in erythrocyte lipid peroxidation associated with significant (P < 0.001) depletion of reduced glutathione level. Superoxide dismutase and catalase activity was suppressed by NaF treatment by 3.069 and 2.3 fold when compared with untreated control groups. Pretreatment of rats with M3OMG or vitamin C afforded protection against NaF-induced oxidative stress as assessed through the measured oxidant/antioxidant markers. Conclusion This finding provided in-vivo evidence for the therapeutic potential of M3OMG in combating fluoride-induced oxidative damage in cellular systems.