This study was to investigate the role and mechanism of liraglutide in the treatment of diabetic nephropathy (DN) mice. A mouse model of streptozotocin-induced DN was established. The mice were intraperitoneally injected with liraglutide at a dose of 200 mu g/kg for 6 weeks. The expression of interleukin-6 (IL-6), tumor necrosis factor (TNF), and nuclear factor kappa B (NF-kappa B) messenger RNA (mRNA) in renal tissue of mice was examined by real-time quantitative polymerase chain reaction (PCR). Meanwhile, the expression of IL-6 and TNF protein in renal tissue of mice was detected by western blot, while the expression of NF-kappa B protein in renal tissues of each group was detected by immunofluorescence. After 6 weeks of intervention, the blood glucose (GLU), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and weight of the liraglutide group were significantly lower than those of the DN group (P < 0.01 or P < 0.05), whereas high-density lipoprotein (HDL) was significantly increased (P < 0.05). At the same time, the microscale albuminuria (MAU) and N-acetyl-beta-d-glucosaminidase (NAG) in the liraglutide group were significantly lower than those in the DN group (P < 0.05). Moreover, the urea (UR), creatinine (CR), and uric acid (UA) in the liraglutide group were significantly lower than those in the DN group (P < 0.01 or P < 0.05). In addition, the mRNA and proteins of IL-6, TNF, and NF-kappa B in the liraglutide group were significantly lower than those in the DN group (P < 0.05). In conclusion, the mechanism of liraglutide in the treatment of DN may be related to the inhibition of the expression of genes and proteins of inflammatory factors.