Objective: In this study, the ameliorative potential and antioxidant capacity of treated with different doses of Bryonia multiflora extract (BE) was investigated using histopathological and immunohistochemical changes in pancreatic beta cells, liver and kidney tissues of streptozotocin (STZ)-induced diabetic rats. Material and Methods: A total of forty-two healthy adult Wistar albino male rats were divided randomly into six groups as Control (C); Diabetes mellitus (DM); DM+Akarboz 20 mg/kg; DM+100 mg/kg BE extract (BE1); DM+200 mg/kg BE extract (BE2); DM+400 mg/kg BE extract (BE3). Experimental diabetes was established by a single-dose [45 mg/kg, intra-peritoneal (i.p)] STZ injection. Essential dosages of BE extracts and Akarboz were applied with gastric gavage for 21 day. Blood glucose levels were recorded throughout the all experiment period. Results: Histopathological studies showed that hepatorenal and pancreatic protection by depending on the dose level of BE extracts was further supported by the almost normal histology in DM+BE extract-treated group as compared to the degenerative changes such as disorder of architectural structure, inflammatory cell infiltration, hydropic degeneration and necrosis in pancreas, liver and kidney tissues of STZ-treated rats. Immunohistochemical investigation revealed that STZ-induced degenerative changes in beta-cells in the pancreas of the diabetic rats has reduced insulin immunoreactivity. On the other hand, insulin immunoreactivity in the beta cells of pancreas of BE -treated diabetic rats has significantly increased. Additionally, Glutathione peroxidase 1 (GPx1) immunoreactivity was lower in the tissues of diabetic rats (DM group) compared to the other groups. Conclusion: In conclusion, BE extract has a protective effect on tissue damage probably due to its antioxidant activity and possess the ability to regenerate beta-cell in STZ-induced diabetic rats.