Saponins as small organic molecules and polysaccharides as biomacromolecules are the main bioactive substances of Momordica charantia L. (M. charantia) with anti-hyperglycemic activities. This study was aimed to fully compare the antidiabetic effects and the potential mechanism of saponins (SMC) and polysaccharides (PMC) from M. charantia in STZ-induced type 2 diabetic mice with high-fat diet. Three dosages of SMC (L-SMC: 20 mg/kg, M-SMC: 40 mg/kg, H-SMC: 80 mg/kg) have a certain of therapeutic effect on type 2 diabetic mice, and M-SMC (40 mg/kg) is the optimal dosage for the prevention and treatment of diabetes. The results showed that oral administration of SMC, especially M-SMC (40 mg/kg) compared to PMC (500 mg/kg), could significantly restore the body weight, reduce fasting blood glucose levels, ameliorate insulin resistance and increase the proportion of hepatic phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK)/total protein. The above results proved that hypoglycemic mechanism of SMC might involve in the AMPK/NF-κB signal pathway by activating AMPK phosphorylation and regulating the energy metabolism of the body. However, oral administration of PMC could significant improve the antioxidant capacity by increasing the level of SOD and decreasing the level of MDA, and alleviate the STZ-induced organ tissues (kidney and pancreas), which proved that the hypoglycemic mechanism of PMC might by repairing the pancreatic β cells damaged by STZ.