This study aimed to explore the protective effects and underlying mechanisms of black corn polysaccharide on renal injury in diabetic mice. A murine diabetes mellitus model was established using intraperitoneal streptozocin injection, followed by black corn polysaccharide intervention. Urine albumin content, urine albumin/creatinine ratio, serum creatinine (SCr), blood urea nitrogen (BUN), triglyceride (TG), total cholesterol (TC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) levels were measured using biochemical assay kits. Histopathological changes in kidney tissues were assessed through HE, PAS, and Masson staining. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10). Western blot analysis was performed to determine the protein expression of phosphorylated p65 (p-p65), p65, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). The results showed that compared with those in the model group, the levels of SCr, BUN, MDA, TG, and TC in the high-dose black corn polysaccharide group were reduced by 56.41%, 54.89%, 45.34%, 13.10%, and 11.85%, respectively. Additionally, the 24 h urinary protein content and UACR levels decreased (P<0.01), while the activities of SOD, GSH-Px, and CAT increased (P<0.01). The renal tubules were neatly arranged, and the degree of fibrosis and glycogen deposition in the kidney tissue was reduced. The serum levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α were reduced by 36.85%, 30.77%, and 36.85%, respectively, while the level of the anti-inflammatory factor IL-10 was increased by 32.46% (P<0.01). The expression of Nrf2 and HO-1 was increased by 68.33% and 77.09%, respectively, while the expression of p-p65/p65 was decreased by 35.22%. These results indicate that black corn polysaccharide exerts a considerable protective effect on diabetic kidney damage, offering a scientific basis for the treatment of patients with clinical diabetic nephropathy.