Background: Spexin is a peptide hormone that was expressed in brain regions and peripheral tissues of many species including human and rat. Several studies investigated its blood level changes with obesity and type 2 diabetes, but few studies assessed its effect on cardiometabolic, histological and morphometric changes in diabetes with some controversies in their results. Objective: To explore the effect of spexin treatment on cardiometabolic, histological and morphometric changes of pancreas and heart tissue in obese type 2 diabetic rats, and the possible mechanisms involved. Materials and Methods: Thirty adult male albino rats were divided randomly into 5 equal groups; control (fed ordinary laboratory chow along this 8 weeks’ study), diabetic [fed high fat diet along this 8 weeks’ study, but at the start of the 4th week, overnight fasted rats were injected with a single streptozotocin injection intraperitoneally (40 mg/kg body weight, dissolved in 0.01M citrate buffer, pH 4.5) to induce diabetes], diabetic metformin-treated [rats were managed as in diabetic group and in addition to that, metformin was given orally (300 mg/kg/day) by oral gavage to rats for 4 weeks from the start of 5th week to the end of 8th week], diabetic vildagliptin treated [rats were manipulated as in diabetic group and in addition to that, vildagliptin was given orally (10 mg/kg/day) using oral gavage to rats for 4 weeks from the start of 5th week to the end of 8th week], and diabetic spexin treated [rats were managed as in diabetic group and in addition to that, spexin dissolved in normal saline was injected intraperitoneally (35 μg/kg/day) for 4 weeks from the start of 5th week to the end of 8th week] groups. For histological, immunohistochemical and morphometric examinations, fresh heart and pancreatic specimens were collected from rats that were sacrificed. Results: In diabetic group, a significant increase was detected in final body mass index, serum glucose, serum insulin, homeostasis model assessment-insulin resistance, serum total cholesterol, serum triglycerides, serum low density lipoprotein, atherogenic index, serum dipeptidyl peptidase-IV, serum tumor necrosis -1 beta, serum malondialdehyde, serum lactate dehydrogenase, serum creatine kinase-myoglobin binding and mean arterial blood pressure, with a significant decrease in homeostasis model assessment-dismutase and serum spexin in comparison to that in the control group. With spexin treatment (as well as with the administration of standard drugs metformin and vildagliptin), all these changes were reversed significantly in comparison with those in the diabetic group. Diabetes induced histopathological changes in cardiac muscle and pancreatic structure which were ameliorated by treatment with spexin as well as with the standard anti-diabetic drugs (metformin and vildagliptin). The morphometric analysis confirmed the histopathological results, as a statistically significant difference was detected in area percent of collagen deposition, area percent of insulin immune-reaction in pancreas and cardiac muscle Bax expression between