The present study was performed to examine the effects of garlic on obesity and blood lipid profiles in high-fat induced obesity mice model, and to elucidate the molecular mechanisms responsible for such effect. C57BL/6 mice were fed a standard diet (STD) or high-fat diet (HFD) for 5 weeks to induce obesity. Mice were then randomly divided into four groups with 10 mice per group, and fed experimental diet for 4 weeks; STD group, HFD group, HFD containing 2% or 4% garlic group (HFD + G2 or HFD + G4, respectively). Administration of garlic significantly reduced HFD-induced body weight, epididymal fat accumulation, hyperlipidemia and hypercholesterolemia. Consequently, the atherogenic indexes were reduced by 83% and 91%, respectively, in 2% and 4% garlic supplemented group. Liver steatosis induced by HFD was ameliorated by garlic supplementation. Furthermore, garlic affected the down regulation of expression patterns of epididymal adipose tissue genes such as peroxisome proliferator-activated receptor γ (PPARγ), acetyl CoA carboxylase (ACC), adipose specific fatty acid binding protein (aP2), and glycerol-3-phosphate dehydrogenase (GPDH). These results suggest that garlic may have a potential benefit in preventing obesity.