Objective To explore the therapeutic effect of pancreatic kininogenase combined with irbesartan on Diabetic Nephropathy (DN). Methods: 82 patients with DN admitted to our hospital from October 2022 to August 2024 were selected as the research subjects. The patients were divided into the control group and the observation group by random number table method, with 41 cases in each group. The control group was treated with irbesartan. The observation group was treated with irbesartan combined with pancreatic kininogenase. The Blood Glucose [Fasting Blood Glucose (FBG), 2-hour Postprandial Blood Glucose (2hPG)], renal function [Blood Urea Nitrogen (BUN), Creatinine (Cr)] and adverse reactions of the two groups were analyzed and compared. Results: After treatment, the blood glucose levels of 2hPG and FBG in both groups were significantly lower than those in the control group, and the 2hPG and FBG in the observation group were significantly lower than those in the control group (P < 0.05). After treatment, the levels of Cr and BUN in both groups were significantly lower than those in the control group, and the levels of Cr and BUN in the observation group were significantly lower than those in the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion: The application of pancreatic kininogenase combined with irbesartan in the treatment of DN patients can reduce the blood glucose level of patients, improve their renal function, and has relatively high safety.