In this study, we evaluated the antihyperglycemic effect of an flavorzyme hydrolysate prepared from Meretrix lusoria (ML-FLOP) with low (150 mg/kg B.W.) and high concentration (300 mg/kg B.W.) in obese-diabetic model ob/ob mice. ML-FLOP suppressed the rise in serum glucose, total cholesterol, LDL-cholesterol, triglyceride concentrations and the hepatic triglyceride level as compared with those in the control group. Moreover, ML-FLOP treatment suppressed the rises in fasting blood glucose level and improved the impaired glucose tolerance in ob/ob mice. The hepatic GSH content and antioxidant enzyme activities were significantly increased in the ML-FLOP group. Histopathology of ML-FLOP-treated mice showed less hepatic fatty change, macro steatosis, and relieved the size of adipocytes in a concentration-dependent manner. In addition, ML-FLOP indicated profound inhibitory effects on adipogenesis dose-dependently by down-regulating expression levels of adipogenesis-related proteins SREBP-1, ACC, and FAS. Furthermore, ML-FLOP treatment was demonstrated to improve expression of hepatic gluconeogenesis- and lipogenesis-related genes in terms of glucose and lipid metabolism.