Diabetes mellitus is a group of most common endocrine disease characterized by hyperglycemia. Dendropanax morbifera Leveille is a Korean endemic species in the family Araliaceae, and distributed in the south-western area and Jeju island, Korea. This plant has been used in traditional medicine for the treatment of headache, dysmenorrhea, infectious and skin diseases. We evaluated the anti-diabetic activity of the extract and solvent fractions of D. morbifera aerial part in zebrafish models for type 1 and 2 diabetes. Type 1 diabetic zebrafish model was induced by alloxan, which cause pancreatic β-cell necrosis. Type 2 diabetic zebrafish model was induced by insulin. Exposure to excess insulin can induce insulin resistance typical of type 2 diabetes. The CH2Cl2 fractions of M. morbifera which showed the strongest anti-diabetic activity was subjected to activity-guided fractionation, and dendropanoxide was isolated from the CH2Cl2 fraction. Dendropanoxide revealed potent ameliorative effect on pancreatic islet damage in zebrafish for type 1 and 2 diabetic models, respectively. The compound was investigated inhibitory activities on PTP1B, α-glucosidase and DPP-4. PTP1B was significantly inhibited by dendropanoxide.