Objective: To investigate the efficacy of applying nifedipine and irbesartan hydrochlorothiazide synergistic treatment in elderly patients with hypertension combined with diabetes mellitus and the effect on serum inflammatory factors. Methods: From May 2022 to April 2024, 100 cases of elderly patients with hypertension combined with diabetes mellitus diagnosed and treated in the hospital where we were located were selected, and divided into observation group and control group by randomized numerical table method, 50 cases each. Both groups were treated with conventional symptomatic treatment, while the control group was treated with nifedipine and the observation group was treated with nifedipine + irbesartan hydrochlorothiazide. Comparison of clinical efficacy and safety, before and after the treatment of blood glucose [2h postprandial glucose (2hPG), fasting glucose (FPG)], blood pressure [systolic blood pressure (SBP), diastolic blood pressure (DBP)], serum inflammatory factors [tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), C-reactive protein (CRP)]. Results: The total effective rate of treatment in the observation group (96.00%) was higher than that in the control group (82.00%) (P < 0.05); after 3 weeks of treatment, SBP, DBP, 2hPG, FPG, TNF-α, IL-8, and CRP decreased in the two groups compared with the pre-treatment period, and were lower in the observation group (P < 0.05); the differences in the incidence of adverse reactions between the two groups after the use of medication were not statistically significant when comparing the rates of the two groups (P＞ 005). Conclusion: The synergistic treatment of nifedipine and irbesartan hydrochlorothiazide in elderly patients with hypertension combined with diabetes mellitus has a precise therapeutic efficacy, which can effectively regulate the body"s blood glucose and blood pressure levels, and also reduce the impact of the disease on the serum inflammatory factor, which will not cause serious adverse reactions after the use of the drug, and has a high degree of safety.