Objective: To investigate the effect of pancreatic kininogenase combined with benazepril on diabetic nephropathy (DN) patients. Methods: The clinical data of 106 patients with DN admitted to our hospital from June 2022 to March 2024 were retrospectively collected. Patients were divided into control group (53 cases, benazepril treatment) and observation group (53 cases, pancreatic kininogenase combined with benazepril treatment). The clinical efficacy, renal function index [serum creatinine (Scr) level, blood urea nitrogen (BUN), serum creatinine (SCR) level, UAER, 24h UTP], hemorheological indexes [low blood viscosity (LBV), high blood viscosity (HBV), plasma viscosity (PV), low blood viscosity (LBV), fibrinogen (FIB)], serum associated cytokine levels [interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), advanced oxidized protein products (AOPP), superoxide dismutase (SOD)] and adverse reactions were analyzed and compared between the two groups. Results: The total effective rate of observation group was significantly higher than that of control group (P < 0.05). After treatment, the levels of Scr, BUN, 24h UTP and UAER in both groups were significantly lower than before treatment, and the levels of Scr, BUN, 24h UTP and UAER in observation group were significantly lower than those in control group (P < 0.05). After treatment, the levels of LBV, HBV, PV and FIB in both groups were significantly lower than before treatment, and the levels of LBV, HBV, PV and FIB in the observation group were significantly lower than those in the control group (P < 0.05). After treatment, the levels of AOPP, IL-6 and hs-CRP in both groups were significantly decreased compared with before treatment, and the levels of SOD were significantly increased compared with before treatment (P < 0.05). In addition, the levels of AOPP, IL-6 and hs-CRP in the observation group were significantly lower than those in the control group, and the level of SOD was significantly higher than that in the control group (P < 0.05). There was no significant difference in the total incidence of adverse reactions between the two groups (P > 0.05). Conclusion: Pancreatic kininogenase combined with benazepril in the treatment of DN can improve clinical efficacy, improve renal function and hemorheology, and reduce the level of serum related cytokines, with high safety.