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• Coixol-based derivatives were designed and synthesized. • Screened in-vitro for insulin secretagogue effect. • The compound 14a and 34 were identified as most potent in insulin secretory effect. • The in vivo antidiabetic effect was significant in reduction of plasma glucose and total cholesterol level. • Histopathological examination showed improvement in the pancreatic tissues. Natural products have great potential for structural modifications to achieve the desired biological effect. In addition, these are considered safer, less expensive, and easily accessible compared to synthetic drugs. The natural compound coixol is a potent insulin secretagogue, obtained from the Plant parts of Scoparia dulcis and Coix lacryma jobi. In the present research work, we synthesized coixol-based derivatives that could potentially emerge as successful antidiabetic agents. Our previous work explains exclusive molecular docking studies based on the natural product coixol, which led to the current selection of twelve molecules comprising 2-benzoxazolinones, 2-benzimidazolinone, and benzimidazole-2-thiones with a good binding affinity toward ATP-sensitive potassium channel. All the synthesized molecules were screened for in vitro studies using a rat insulin ELISA assay. Wherein, Compounds 14a and 34 were identified as the most potent molecules with percentage insulin secretory concentrations of 162.43 and 227.16 µU/mL respectively which was reportedly higher than the standard drug Glibenclamide. The in vivo antidiabetic effect was checked using the streptozotocin-induced Type-II diabetes rat model, which revealed that test compounds 14a and 34 significantly reduced plasma glucose and total cholesterol levels and a marked increase in plasma insulin response was observed in diabetic rats. The histopathological examination at the end of the protocol also showed an improvement in the pancreatic tissue of diseased animals treated with test compounds 14a and 34. Thus, this research work indicates that the synthesized derivatives of coixol, 14a and 34 have good potential to be used for treating and managing Type-II diabetes in the future. [Display omitted] [ABSTRACT FROM AUTHOR]