The seed coat extracts of adzuki beans and black soybeans have high antioxidant properties, suggesting health-promoting effects. However, there are few data on the activity of fermented adzuki beans or black soybeans in vivo. This study examined the effects of adzuki beans and black soybeans in mice fed a high-fat diet. Adzuki beans and black soybeans were fermented with soybeans and rice koji for 6 months (miso) and compared with similarly fermented soybeans. Adzuki beans and black soybeans demonstrated higher antioxidant activity compared to soybeans, as evidenced by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In the in vivo experiments, mice were fed for 5 weeks with a high-fat diet supplemented or not with 10% adzuki bean miso, 10% black soybean miso, or 10% soybean miso. Dietary supplementation with adzuki beans and black soybeans significantly decreased serum aspartate transaminase (58.6% and 62.6%, respectively) and lipid peroxidation in the liver (42.8% and 40.8%, respectively) compared to the soybean control group. Furthermore, mice receiving adzuki beans demonstrated a significant decrease in serum cholesterol (31.0%) and increase in fecal bile acid content (40.0%) compared to the soybean-fed mice. These results indicate that dietary supplementation with adzuki beans and black soybeans characterized with high antioxidant activity may exert health beneficiary effects such as liver protection and reduction of total cholesterol.