CONTEXT: Quercetin is a well known aglycone flavonoid that is widely found in different food sources. OBJECTIVE: In this study, the in vivo neuroprotective potential of quercetin against sodium fluoride-induced oxidative stress was evaluated. MATERIALS AND METHODS: Wistar rats were divided into five treatment groups and then subjected to daily intraperitoneally treatment with quercetin (at 10 and 20 mg/kg body weight), vitamin C (at 10 mg/kg), or vehicle. After a 1 week treatment period, all groups except saline treated (normal group), were intoxicated with sodium fluoride (NaF) for 1 week. Rat brains were then removed and homogenized for measurement of antioxidant markers including superoxide dismutase (SOD), reduced glutathione, catalase, and lipid peroxidation final products. RESULTS: The thiobarbituric acid reactive substances (TBARS) levels in the heart homogenate of sodium fluoride treated rats (42.04 ± 2.14 nmol MDA eq/g tissue) increased compared to the normal rats (35.99 ± 1.08 nmol MDA eq/g tissue). Animals which were pretreated with quercetin at 20 mg/kg for 1 week prior to sodium fluoride intoxication showed significant reduction in the TBARS level (36.13 ± 1.12 nmol MDA eq/g tissue). Also, pretreatment with quercetin (20 mg/kg) restored the SOD and catalase activities and modified the level of reduced glutathione compared with the control group (p > 0.05). DISCUSSION AND CONCLUSION: The present study revealed a potent neuroprotective potential of quercetin against NaF-induced toxicity.