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The effect of 21% fructose drinking water (FDW) (w/v) on some parameters of metabolic syndrome, hepatic, and skeletal muscular histology of rats was studied using standard techniques. Twenty male albino rats were divided into four groups of 5 rats each in this in vivo study. Group I received distilled water, group 2 received FDW, group 3 received FDW and metformin (300 mg/kg body weight daily, orally), group 4 received FDW and 1% tert‐butylhydroquinone feed. FDW changed the serum leptin, triacylglycerol, very low‐density lipoprotein, and C‐reactive protein levels of the rats, inducing hypertriglyceridemia, oxidative stress, and inflammation in their liver (but not the skeletal muscle) and insulin resistance which were modulated with metformin and tBHQ as corroborated by liver and muscle histology. The study reveals the potentials of metformin and tBHQ in mitigating hepatic and skeletal muscular morphological changes arising from exposure to high fructose drinks. Practical applications There has been an increase in the global consumption of fructose (either as a sweetner in beverages or soft and carbonated drinks) in the last few decades and this has been positively correlated with the global increase in metabolic complications. Regular intake of fructose contributes to the pathogenesis of lipid disorders, oxidant stress, and chronic inflammation, which are linked with the metabolic syndrome components (MetS) (obesity, insulin resistance, and cardiovascular diseases) as well as increased morbidity and mortality. Given that the approaches that have been applied to treat the MetS have not been able to totally arrest it, currenty study which showed that tBHQ abrogated fructose‐induced insulin resistance, dyslipidemia, hepatic, and skeletal muscular pathology in the rats places tBHQ in the spotlight as a nutraceutical that could be of relevance in mitigating high dietary fructose‐induced hepatic and skeletal muscular pathology.