This study investigated the antiobesity effect of garlic in diet-induced obese mice. Male C57BL/6J mice were fed a high-fat diet (45% fat) for 8 wk to induce obesity. Subsequently, they were fed a high-fat control diet, high-fat diets supplemented with 2%, or 5% garlic (wt:wt) for another 7 wk. Dietary garlic reduced body weight and the mass of various white adipose tissue deposits and also ameliorated the high-fat diet-induced abnormal plasma and liver lipid profiles. Garlic supplementation significantly decreased the mRNA levels of adipogenic genes in white adipose tissues (WAT). However, consumption of garlic increased the expression of mRNA for uncoupling proteins in brown adipose tissue (BAT), liver, WAT, and skeletal muscle. Mice treated with garlic maintained a significantly higher body temperature than untreated mice during a 6-h, 4°C cold challenge and, notably, AMP-activated protein kinase (AMPK) activity was stimulated in BAT, liver, WAT, and skeletal muscle. These results suggest that the antiobesity effects of garlic were at least partially mediated via activation of AMPK, increased thermogenesis, and decreased expression of multiple genes involved in adipogenesis.