Introduction and aim of the work: Sorafenib (Nexavar) is an oral inhibitor of multi-kinase proteins approved in 2005 for treatment of metastatic renal cell and advanced hepatocellular carcinoma. It causes many metabolic side effects, including diarrhea, hypertension, hand-foot skin reaction, and fatigue. This study aims to detect the histopathological changes of the rat pancreas under acute and chronic sorafenib treatment. Methods: The rats were divided into 3 groups. • Group 1: served as control (rats were orally administrated with ml of normal saline for a month. • Group 2: (acute group) Rats of this group were treated with the multikinase inhibitor sorafenib (60 mg/kg body weight/day) for 15 days by gavage. • Group 3: (chronic group) Rats of this group were treated with the multikinase inhibitor sorafenib (60 mg/kg body weight/day) for 30 days by gavage. Animals were sacrificed and specimens from the pancreatic tails were processed for histopathological, histochemical; by estimation of total carbohydrates, total mucine & collagen fibers and immunohistochemical studies by estimation of Anti-insulin antibody. Results:In treated animals, there were histopathological and histochemical alterations Immunohistochemical staining with anti-insulin antibody showed strong staining of the islets of treated animals with highly significant ((P<0.05)) increase than control rats. Conclusion: Sorafenib treatments caused pathological and toxic changes in the pancreas which need to careful using of this drug and may use of natural antioxidants will be useful.