The herbal composition Gyeongshingangjeehwan 18 (GGEx18), which is composed of three herbs, Laminaria japonica Aresch (Laminariaceae), Rheum palmatum L. (Polygonaceae), and Ephedra sinica Stapf (Ephedraceae), has been used as an anti-obesity drug in Korean local clinics. Thus, we investigated whether GGEx18 regulates obesity by suppressing appetite in high fat diet-induced obese C57BL/6J mice. Administration of GGEx18 to obese mice for 9 weeks significantly decreased body weight gain, epididymal adipose tissue weight, and food efficiency ratio. GGEx18 also caused a significant decrease in the circulating levels of leptin, which were increased by about 450% in obese control mice compared with normal lean mice. Concomitantly, GGEx18 decreased mRNA levels of a potent appetite-stimulating hormone neuropeptide Y, but increased an appetite-suppressing hormone pro-opiomelanocortin mRNA levels. These results suggest that GGEx18 may prevent obesity through regulating appetite in nutritionally obese mice.