Abstract: This study investigated the therapeutic effects and molecular mechanisms of chicory root polysaccharides (CPS) on diabetic nephropathy (DN). Using db/db mice to establish a DN model, mice were randomly divided into normal control group, model group, CPS high-, medium-, and low-dose groups (800, 400, 200 mg/kg), and positive control group (irbesartan), with administration via gavage for 8 weeks. After 8 weeks, urine samples were collected for protein and creatinine determination. Serum samples were used to measure serum creatinine (Scr), blood urea nitrogen (BUN), cystatin C (Cys-C), β2-microglobulin (β2-MG), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Enzyme-linked immunosorbent assay (ELISA) was employed to detect inflammatory factors TNF-α, IL-1β, and IL-6 in serum and kidney tissues. HE staining was performed to analyze kidney tissue pathological changes. Immunohistochemistry was used to detect positive expressions of TGF-β1, Smad2/3, α-SMA, and Collagen-I. Results showed that CPS exhibited a significant dose-dependent improvement in various indicators, significantly (P<0.01 or P<0.05) ameliorating DN mice's kidney function parameters, including serum creatinine, urea nitrogen, cystatin C, and β2-microglobulin levels. Histopathological examination revealed that CPS could improve pathological ultrastructural changes such as glomerular hypertrophy, mesangial proliferation, and foot process fusion. CPS also significantly (P<0.01 or P<0.05) reduced blood lipid levels and inflammatory factor expressions, improving lipid metabolism disorders. Immunohistochemical analysis discovered that CPS inhibited the activation of TGF-β1/Smads signaling pathway, significantly (P<0.01 or P<0.05) reducing the expression of fibrosis effector molecules like α-SMA and Collagen-I. The study confirmed that CPS possesses multiple protective effects, including preserving glomerular filtration function, maintaining renal tubular epithelial cell integrity, and exhibiting anti-fibrotic properties, thereby providing crucial scientific evidence for the development and utilization of chicory root as a functional food ingredient.