Obesity remains one of the main issues in public health. It is a sign of menopause in women, in addition to being connected to metabolic problems. This work was constructed to assess the in Vivo possible therapeutic effects as well as physiological mechanisms of Salvia officinalis extract and Orlistat in preventing obesity. The obesity model was created by rats ovariectomy, a three-month postoperative period was applied to reach a remarkable decline in estrogen levels and ensuing obesity. Ovariectomy (Ovx) rats were treated with Salvia officinalis extract (10 ml /Kg orally) and Orlistat (12 mg/kg orally) daily over 6 weeks. SOE and OR-treated rats exhibited significant decreases in body weight, visceral fat, blood glucose, triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), liver enzymes (AST, ALT), Malondialdehyde (MDA) content, leptin, adiponectin, and pancreatic lipase with a considerable increase in high-density lipoprotein (HDL), total glutathione (GSH), and total antioxidant capacity (TAC) comparable to OVX rats. The histopathological analysis also supported these findings. Co-administration of SOE and OR regained body weight, liver, and adipose histological changes to levels close to normal and reversed all the biochemical markers examined. SOE and OR exhibited anti-obesity potential in OVX rats as evidenced by improving insulin sensitivity, inhibiting lipid synthesis in adipocytes, and reducing oxidative stress according to normal lipid levels. SOE provides a secure and efficient treatment for obesity when used alone or in combination with orlistat, particularly menopausal-related obesity.