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Abstract Globally, obesity has become one of the major health problems. This study was conducted to evaluate the anti-obesity potential of Cymbopogon schoenanthus methanolic extract (CS) in rats. Fifty male Wistar rats of six to eight weeks-old, 100–120 g body weight (BW) were randomly assigned into 5 groups (n = 10): Control group was fed basal diet. CS-group was supplied with basal diet and orally given CS (200 mg/kg BW) for 12 weeks. HFD-group was fed a high fat diet (HFD) for 18 weeks. HFD + CS-group was fed on HFD and CS. HFD then CS-group was fed HFD for 12 weeks then, shifted to basal diet and CS for another 6 weeks. Phytochemical analysis of CS indicated the presence of various terpenes and flavonoid compounds. Among the compounds characterized are quercetin, apigenin, luteolin, orientin, eudesmene, cymbopogonol, caffeic acid, coumaric acid and linolenic acid. Supplementation of HFD significantly increased the body weight, serum level of total cholesterol, triacylglycerol, low density lipo-protein, very low-density lipoprotein, glucose, activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In addition, HFD up-regulated the protein expression of uncoupling protein (UCP)-1 in both brown and white adipose tissue; and hepatic mRNA expression of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2. However, it decreased serum level of HDL, protein expression level of UCP-1 in both brown and white adipose tissue. Treatment of HFD-fed animals with CS extract either concurrently (HFD + CS-group), or after obesity induction (HFD then CS-group) significantly reversed all HFD-induced alterations in body weight; food intake; serum biochemical profile (including hyperglycemia, dyslipidemia); and tissue gene expressions. These results indicate that CS methanolic extract ameliorated HFD-induced obesity, serum biochemical, hepatic, and adipose tissue gene expression alterations. CS extract accomplished these effects mostly through its various identified bioactive compounds which have been proven to have anti-obesity and anti-diabetic activities. Keywords: Cymbopogon schoenanthus; NMR; LCMSMS; Flavonoids; Terpens; Obesity; Uncoupling protein 1; Sterol regulatory binding protein |