Hyperglycemia is one of the major causes for various types of diseases and clinical complications. 4-Morphionylphenyl-6-arylpyrimidine-2-imines (8a-k) are good sources of medicinal compounds, and are novelty used to control diabetes mellitus. In this study the compounds (8a-k) are investigated by the molecular docking analysis, in vitro enzyme inhibitory activity, and in vivo antihyperglycemic activity. The molecular docking results of compounds (8a-k) suggest one potential agent as 1v4s protein activators for future hyperglycemic therapeutics. The compounds (8a-k) show the significant inhibiting activity of the alpha-amylase enzyme at the concentration of (100 μg/ml) as compared to the alpha-glucosidase enzyme (100 μg/ml). The in vivo antihyperglycemic activity of compounds (8a-k) 10 mg/kg (po) against nicotinamide 120 mg/kg (po)-streptozotocin 60 mg/kg/b.w (ip)-induced diabetes in healthy adult male albino Wistar rats are estimated and the entire designed compounds (8a-k) exhibits significant antihyperglycemic activity. These results suggest that the compounds (8a-k) may be a potential source for the development of new oral antihyperglycemic agent.