The aim of this study is to determine the anti-obesity effects of genistein and exercise, separately and in combination, in mice. Fifty male C57BL/6J mice were divided into 5 treatment groups: normal diet (ND), high fat diet (HD), high fat diet with exercise (HD+Ex), high fat diet with 0.2% genistein (HD+G), high fat diet with 0.2% genistein, and exercise (HD+G+Ex). They were allowed free access to feed and water, and exercised mice engaged in swimming on a regular basis for 12 weeks. Genistein supplemented mice gained less weight, had lower energy intake, better lipid profiles, and lower leptin than the HD mice. Furthermore, when genistein was combined with exercise (HD+G+Ex) the effects were even greater. HD, HD+Ex, and HD+G mice exhibited increased hepatic CPT-1 mRNA expression. Therefore, genistein and exercise has anti-obesity effects, as shown by changes in body weight, fat accumulation, energy intake, and leptin levels.