Background: Oxytocin (OT) has effects on uterine contraction and milk ejection, but growing evidence suggests that OT plays an important role in the regulation of energy homeostasis and development of obesity. Objective: The aim of this study was to investigate the effect of OT in modifying metabolic changes and atherosclerosis in diet-induced obesity rat model and its possible mechanisms. Materials and methods: A total of 30 male rats and 60 female adult albino rats were divided into three main groups: male, female, and the ovariectomized group. Each group was subdivided into three equal groups: control, high-fat diet (HFD) fed, and HFD-OT-treated groups. Body mass index, body weight gain and mean arterial blood pressure were measured. Serum cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein-cholesterol, nitric oxide, reduced glutathione, malondialdehyde, C-reactive protein, insulin, and glucose were estimated, and atherogenic index was calculated. Aortic artery histopathology was studied. Results: In all groups, OT treatment to HFD-fed rats decreased body mass index and weight gain and improved hyperlipidemia, high glucose, low insulin levels, and elevated mean arterial blood pressure caused by HFD. It showed antioxidative stress activity as indicated by decreased C-reactive protein and malondialdehyde (MDA) and elevated nitric oxide and glutathione levels. OT treatment reveled anti-inflammatory action as indicated by aortic histopathology. Conclusion: OT administration to HFD-fed rats reduced body mass index and weight gain and improved metabolic changes associated with lipid profile, glucose tolerance, and blood pressure. In addition, it dramatically ameliorated the aortic atherosclerotic changes. This effect is due to its antioxidative stress activity and anti-inflammatory action, and this effect was more prominent in female and ovariectomized female rats. Further studies are recommended for more evaluation of other mechanisms that explain the metabolic action of OT and to clarify the difference in its action on sex and other species of experimental animals.