Background: Hippocratea velutina (HV) is a novel plant folklorically used for lowering blood glucose, hence a potential source of new antidiabetic medication. Objective: The study evaluated the anti-diabetic potentials of the methanol extract of Hippocratea velutina leaf and its toxicity profile in mice and rats. Methods: Acute and subacute toxicity tests of the plant extract were carried out by using a modified OECD guideline. Its antidiabetic activity in streptozotocin-induced diabetic rats at 50, 150, and 300 mg/kg for 28 days was assayed, while glibenclamide (5 mg/kg) and distilled water were the positive and negative controls, respectively. Histopathological examination of vital organs was also carried out. Results: Preliminary phytochemical screening of the leaf extract showed the presence of tannins, flavonoids, saponins, alkaloids, terpenoids, deoxy-sugars, and anthraquinones in HV. The extract had LD50 greater than 2000 mg/kg in mice. It had no toxic effects on the haematological and biochemical components from blood samples collected but caused significant blood glucose level reduction in normal rats at 150 and 300 mg/kg. In streptozotocin-induced diabetic rats, the extract elicited a non–dose-dependent antidiabetic effect on day seven at all the tested doses, significantly higher than glibenclamide (10 mg/kg). However, on days 14, 21, and 28, the extract activity at all the tested doses and glibenclamide were comparable. The extract did not affect the liver, brain, kidney, and pancreas histology at 200 mg/kg but caused slight and severe effects on these organs at 400 and 800 mg/kg, respectively. Conclusion: The study concluded that Hippocratea velutina possessed antihyperglycaemic activity and was non-toxic at low doses but could have deleterious effects to the liver and kidney at high concentrations.