The leaf of Nelumbo nucifera Gaertn. (family Nymphaeaceae) has been used for summer heat syndrome as home remedy in Japan and China, and it has recently been used to treat obesity in China. So we investigate the pharmacological mechanism of the anti-obesity effect of Nelumbo nucifera leaves extract (NNE). We examined the effect of NNE on digestive enzyme activity, lipid metabolism and theromogenesis and evaluated the effects of anti-obesity using high-fat diet-induced obesity in mice that were treated with NNE for 5 weeks. NNE caused a concentration-dependent inhibition of the activities of alpha-amylase and lipase, and up-regulated lipid metabolism and expression of UCP3 mRNA in C2C12 myotubes. NNE prevented the increase in body weight, parametrial adipose tissue weight and liver triacylglycerol levels in mice with obesity induced by a high-fat diet. UCP3 mRNA expression in skeletal muscle tended to be higher, when mice were administrated by NNE and were exercised. Therefore, NNE impaired digestion, inhibited absorption of lipids and carbohydrates, accelerated lipid metabolism and up-regulated energy expenditure. Consequently, NNE is beneficial for the suppression of obesity.