Diabetes mellitus is the most common endocrine disease associated with various metabolic disorders. Currently, oral hypoglycemic agents and insulin have serious side effects, so there is a need to find an alternative yet safe anti-diabetic medicine. The present study aimed to determine the hypoglycemic property of the Syzygiumpolycephaloides. Test tube method, thin layer chromatography, qualitative and quantitative analyses revealed the secondary metabolites of the S. polycephaloides leaf extract such as alkaloids, flavonoids, triterpenes, terpenoids, tannins, phenols, and anthraquinones. Hypoglycemic activity was investigated through in vivo assay using mice. The in vivo assay indicates that metformin and the two different concentrations of extracts (500mg/kg and 250 mg/kg) were able to considerably reduce blood glucose level compared to negative control. The blood glucose level before and after the oral administration have significant effect on the blood glucose level of mice (p <0.05). The histopathological observations confirmed the improvement in treated groups compared to the negative control. Histopathological studies further revealed the effectiveness of S. polycephaloides when the reduced islet cells were restored to near-normal conditions to alloxan-induced mice. Therefore, S. polycephaloides has a capability in lowering the blood glucose level.