Objective Obesity threatens to become the foremost cause of chronic disease in the world. Being obese can induce multiple metabolic abnormalities that contribute to diabetes, dyslipidemia, cardiovascular disease, glucose intolerance and other chronic disorders. It is becoming one of the greatest threats to global health in this millennium, with more than 1 billion overweight adults and of those, at least 300 million are clinically obese. Considerable advances have been made in diet, exercise and behavior approaches to treatment for obesity and new drugs with even better profile of pharmacological activity continues to be introduced on a regular basis. Thus, in spite of tremendous development in the field of allopath during the 20th century, plants still remain one of the major sources of drug in the modern as well as traditional system of medicine throughout the world. Methods In this study, we elucidated that Nepetae Spica extract significantly inhibited lipid accumulation during 3T3-L1 adipocyte differentiation. Furthermore, Nepetae Spica extract reduced the body weight gain induced through feeding a high-fat diet to C57BL/6 mice. Results The treatment of Nepetae Spica extract significantly reduced the adipose tissue weight to 2.7/100 g of body weight in high-fat mice. When their adipose tissue morphology was investigated for histochemical staining, the distribution of cell size in the high-fat diet groups was hypertrophied compared with those from Nepetae Spica extract-treated mice. In addition, in Nepetae Spica extract-treated mice, a significant reduction of serum triglyceride and T-cholesterol was observed at to 21% and 17%, respectively. Conclusion The discovery of bioactive compounds from diet or dietary supplementation is one of possible ways to control obesity and to prevent or reduce the risks of various obesity-related diseases. These results support that Nepetae Spica extract is expected to create the therapeutic interest with respect to the treatment of obesity.