Diabetes is usually associated with oxidative stress that causes hepatic and pancreatic tissue injury. This work was carried out to evaluate the effect of Cucumis sativus and Cucurbita maxima methanol extracts on the streptozotocin-induced diabetic hepatic and pancreatic injury in rats. Diabetes was induced in seven equal groups of rats by a single intraperitoneal injection of streptozotocin (40 mg/kg), in addition to the non-diabetic control group. Two diabetic groups were treated with Cucumis sativus methanol extract and two were treated with Cucurbita maxima, each at 200 and 400 mg/kg for 21 days after streptozotocin-induced diabetes. Another diabetic group was treated with both Cucumis sativus and Cucurbita maxima at 200 mg/kg of each. Another group was treated with metformin (200 mg/kg orally). The plant extracts normalized serum liver enzymes activities, oxidative stress markers, and restored serum proteins and lipid profile. They also significantly reduced blood sugar to values comparable to non-diabetic rats. The hypoglycemic effect is also confirmed by the improvement of the immunohistochemical expression of insulin in β-cells of islets of Langerhans. Hepatic and pancreatic protection was also confirmed by the improvement of the histopathological picture as compared to STZ-diabetic rats. The GC-MS analysis revealed the presence of 35 and 34 compounds in the methanol extract of cucumber and pumpkin, respectively. Finally, the methanol extract of cucumber and pumpkin could be beneficial acting synergistically in the protection of the liver and pancreas against diabetes-induced tissue damage.