Background: Exendin-4 is a similar peptide to glucagon - like peptide-1, and can interfere with various receptors of glucagon  like peptide-1and is evaluated for the regulation of blood glucose in diabetes mellitus. Berberine  (BBR) is demonstrated to have a hypoglycemic effect in vitro and in vivo.  Objective: Comparing between the effects of berberine and exendine 4 on adult male diabetic albino rats. Materials and Methods: Thirty two adult male albino rats of local strain were housed in 8 suitable metal cages (20 × 32 × 20 cm for every 4 rats). They were divided into four equal groups: Group I served as a control group, group II was diabetic control, group III was diabetic group   treated with berberine, and group IV was diabetic group received exendin-4. Body weight was measured daily till the end of  the experimental period .Blood samples were collected for measuring fasting glucose, fasting insulin, homeostasis model assessment  insulin resistance ( HOMA –IR), C-peptide, glycosylated hemoglobin (Hb A1c), cholesterol(CHO), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), and high density lipoproteins cholesterol (HDL-c). The pancreas of the sacrificed rats were excised and randomly processed for histological staining and biochemical assays for superoxide dismutase (SOD) and malondialdehyde (MDA).               Results: Alloxan-induced diabetes mellitus was associated with significant higher levels of blood glucose, HOMA –IR, Hb A1c, total cholesterol, triglycerides, LDL-c and pancreatic MDA with significantly lower levels of body weight, insulin, C-peptide, HDL-c and pancreatic SOD as compared with normal control group. Berberine in diabetic rats  produced significant lower levels of body weight, blood glucose, HOMA –IR,  Hb A1c,  total cholesterol,  triglycerides, LDL and pancreatic MDA with significantly higher  levels of insulin , C-peptide , HDL and pancreatic SOD as compared with control diabetic group. Exendin-4 showed significant lower levels of  blood glucose, HOMA –IR, total cholesterol, TG, LDL-c and pancreatic MDA levels, and significant higher levels of insulin , HDL-c, C-peptide and pancreatic SOD as compared with the control diabetic rats. Results of the present study showed that the effects of exendin-4 produced insignificant changes of body weight as compared with control diabetic group. Conclusion: Exendin-4 was more potent in reducing hyperglycemia than berberine, while berberine has a better body weight reduction. Furthermore, berberine treatment significantly increased pancreatic antioxidant enzymes activities as well as exendin-4. Berberine and exendin-4 treatment protected and preserved pancreatic β-cell architecture and integrity.