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The anti-hyperglycemic and antioxidant effects of the Indian herbal formulation Brahmi gritham were studied in streptozotocin-induced diabetic female Wistar albino rats. Diabetes was induced by a single dose of streptozotocin (55 mg/kg body weight [b.w.], i.p.). Estimation of blood glucose levels, liver glycogen content and antioxidant levels were carried out in experimental rats. The tested parameters were compared with those of the glibenclamide (600 μg/kg b.w.) treated group. Molecular docking studies were carried out to analyze the interaction patterns of protein kinase C (PKC) and CD38 of chosen proteins of signal transduction pathways that are significant in the pathogenesis of diabetes against active components of Brahmi gritham. Immunohistochemistry of pancreas revealed that Brahmi gritham was able to restore β-cell mass and function near to that of the normal control. In silico studies showed that apigenin and quercetin showed significant interactions with PKC, while clitorin, bacopaside I and II showed significant interactions with CD38. Quercetin showed highest percentage inhibition of α-amylase enzyme. PRACTICAL APPLICATIONSBrahmi gritham is a traditional polyherbal formulation used in Ayurveda to treat memory disorders. The individual components of this formulation are known to possess significant antioxidant properties and contain several biologically active compounds found to be effective in treating various disorders, including diabetes and obesity. The efficacy of Brahmi gritham in diabetes management has not yet been studied, and therefore, the present study provides insights into the antihyperglycemic potential of this formulation in rat model. In addition, the results of in silico analysis would pave way for better utilization of the flavonoids quercetin and apigenin in diabetes management and in particular microvascular diabetic complications.