To investigate the hypoglycemic effect and potential mechanism of pumpkin polysaccharides and puerarin on type II diabetes mellitus (T2DM) mice, mice were fed a high-fat diet and injected intraperitoneally with streptozotacin to induce T2DM. After eight weeks of drug administration, blood samples were withdrawn from tail veins of mice that had been fasted overnight. The results showed that both pumpkin polysaccharides and puerarin, as well as a pumpkin polysaccharides and puerarin combination, could ameliorate T2DM. The pumpkin polysaccharides and puerarin combination had a synergetic hypoglycemic effect on T2DM mice that was greater than the pumpkin polysaccharides’ or the puerarin’s hypoglycemic effect. Both the pumpkin polysaccharides and the puerarin were found to ameliorate the blood glucose tolerance and insulin resistance of T2DM mice. They showed lipid-lowering activity by reducing the total cholesterol, triglycerides, and low-density lipoprotein levels, and improving the high-density lipoprotein level. They had beneficial effects on the oxidative stress by decreasing the reactive oxygen species and malondialdehyde levels, and increasing the glutathione level and the superoxide dismutase activity. Furthermore, the nuclear factor E2 related factor 2 (Nrf2), heme oxygenase-1, and phosphoinositide-3-kinase (PI3K) levels were upregulated, and the Nrf2 and PI3K signalling pathways might be involved in the hypoglycemic mechanism. The combined administration of pumpkin polysaccharides and puerarin could synergistically ameliorate T2DM.