BACKGROUND/AIMS: Honey and propolis have biological and therapeutic effects in various pathological and clinical conditions such as hyperglycemia and diabetes. However, the combined use of honey and propolis has not been reported. The study evaluated the protective effect of Arbutus unedo honey, propolis and their combination in streptozotocin (STR)-induced hyperglycemia, acute kidney injury (AKI), liver injury, dyslipidemia, and proteinuria in male Wistar rats. METHODS: The study identified physicochemical characteristics, mineral and antioxidant content, and antioxidant activity in honey and propolis. Rats were assigned to five groups, with five rats in each group; control, STR-treated, STR-treated + honey (1g/kg/day), STR-treated + propolis (100 mg/day), and STR-treated + honey and propolis. On day 15, blood glucose, insulin, HBA1c, kidney function tests, liver enzymes, lipid profile, hemoglobin, and urine protein, creatinine, glucose, and electrolytes were analyzed. Liver, pancreas, and kidney tissues were studied histologically. The mineral component in honey and propolis was determined by atomic absorption spectrometry. Honey analysis was performed by HPLC. Chemical characterization of propolis was performed by LC/DAD/ESI-MSn . Measurement of blood and urine parameters was carried out with an automated analyzer (Architect c8000) and XT-1800i Automated Hematology Analyzer. Insulin concentration was determined by Elisa and insulin resistance was estimated by using HOMA-IR. RESULTS: Honey and propolis contain a high quantity of antioxidants and exhibit in vitro antioxidant activity. In STR-treated rats, blood glucose, HBA1c, creatinine, blood urea, liver enzymes, and urine protein significantly increased compared to the control group (P<0.05), while insulin, hemoglobin, and body weight significantly decreased. Histological changes were evident in the pancreas, kidney, and liver tissues. These results indicated AKI, liver injury, and pancreatic injury, which was evident with reducing the number of the island of Langerhans and marked hyperglycemia. The use of honey and propolis significantly (P<0.05) attenuated liver and kidney injury, and proteinuria, and improved level of hemoglobin, HBA1c, and insulin toward the normal range. The combination of honey and propolis was more effective than honey or propolis individually (P<0.05). CONCLUSION: the combination of propolis and honey can prevent STR-induced AKI, liver injury, proteinuria, dyslipidemia, anemia, hyperglycemia, and body weight loss, most likely by their hypoglycemic and antioxidant activities.