The aim of present study was to evaluate the effect of aqueous leaf extract of Annona squamosa with Glipizide in a high fat diet and streptozocin-induced type-2 diabetes. Nine groups (n = 6) of male Sprague-Dawley rats were used for the study, with. Basal blood glucose, urine volume, and body weights were measured and the rate were kept on a high fat diet. After 15 days, streptozocin in sub-diabetic dose (35 mg/kg) was administered to the animals to induce diabetes. With 1 week of consistent hyperglycemia, treatment was initiated. Aqueous extract of Annona squamosa was administered orally at 350 mg/kg body weight alone and in combination with reduced and reducing dose combinations of Glipizide. Blood glucose, body weight, urine volume were measured every 10th day. The elevated blood-glucose level in diabetic rats was controlled better with combination therapy compared with the synthetic drug alone or the herbal stand-alone drug. All the results were statistically significant (P < 0.001). A combination of Annona squamosa along with Glipizide may be helpful in dose reduction of Glipizide up to 50%, reducing the risk of the onset of insulin therapy.