Cirsium setidens Nakai, a wild perennial herb, grows mainly in Gangwon province, Korea, and has been reported to contain bioactive ingredients with various medicinal activities, including the treatment of edema, bleeding, and hemoptysis. However, the potential antiobesity effects of C. setidens Nakai have not been fully investigated. This study evaluated the antiobesity effect of standardized C. setidens Nakai ethanolic extract (CNE) in 3T3-L1 adipocytes and in obese C57BL/6J mice fed a high-fat diet. CNE suppressed the expression of lipogenic genes and increased the expression of lipolytic genes. The antiadipogenic and antilipogenic effects of CNE appear to be mediated by the inhibition of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBP) expressions. Moreover, CNE stimulated fatty acid oxidation in an AMPK-dependent manner. CNE-treated groups of C57BL/6J mice showed reduced body weights and adipose tissue weight and improved serum lipid profiles through the downregulation of PPARγ, C/EBPα, fatty acid binding protein 4 (FABP4), sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (FAS) and the upregulation of adiponectin and carnitine palmitoyltransferase-1 (CPT-1) in obese C57BL/6J mice fed a high-fat diet. These results suggest that CNE may have an antiobesity effect on adipogenesis and lipid metabolism in vitro and in vivo and present the possibility of developing a treatment for obesity with nontoxic natural resources.