The present study aimed to evaluate the therapeutic effects of polysaccharides from Inonotus obliquus (PIO) on streptozotocin- (STZ-) induced diabetic symptoms and their potential mechanisms. The effect of PIO on body weight, blood glucose, damaged pancreatic β-cells, oxidative stresses, proinflammatory cytokines, and glucose metabolizing enzymes in liver was studied. The results show that administration of PIO can restore abnormal oxidative indices near normal levels. The STZ-damaged pancreatic β-cells of the rats were partly recovered gradually after the mice were administered with PIO 6 weeks later. Therefore, we may assume that PIO is effective in the protection of STZ-induced diabetic rats and PIO may be of use as antihyperglycemic agent.