Resveratrol (3,4,5-trihydroxystilbene), a polyphenol and well-known natural antioxidant has been evaluated for its protective effect against fluoride-induced metabolic dysfunctions in rat thyroid gland. Fluoride, the most abundant anions present in groundwater throughout the world, creates a major problem in safe drinking water and causes metabolic, structural, and functional injuries in different organ systems. Sub-acute exposure to sodium fluoride at a dose of 20 mg/kg b.w./day orally to rat for 30 days induces thyroidal dysfunction including suppressed synthetic machinery of the thyroid gland to produce nucleic acids and thyroid hormones, mainly T3 and T4. Other functional changes are alteration of certain metabolic enzyme activities like Na(+)-K(+)-ATPase, thyroid peroxidase, and 5,5'-deiodinase. Structural abnormality of thyroid follicles by fluoride intoxication clearly indicates its thyrotoxic manifestation. Resveratrol supplementation in fluoride-exposed animals appreciably prevented metabolic toxicity caused by fluoride and restored both functional status and ultra-structural organization of the thyroid gland towards normalcy. This study first establishes the therapeutic efficacy of resveratrol as a natural antioxidant in thyroprotection against toxic insult caused by fluoride.