The purpose of this research project was to clarify the influence of Cefoperazone/Sulbactam plus Azithromycin on the alleviation of serum inflammatory factors and the improvement of pulmonary function in patients with severe lower respiratory tract infection, aiming at improving the management of patients with the disease. We first retrospectively analyzed 201 patients with severe lower respiratory tract infection from May 2019 to May 2021, of which 101 patients (research group) were treated with Cefoperazone/ Sulbactam plus Azithromycin and the remaining 100 patients were treated with Cefoperazone/ Sulbactam (control group). The efficacy, incidence of adverse reactions, bacterial clearance rate, recovery (hospitalization time, pulmonary infection control time and fever resolution time), inflammatory factors (interleukin-6, tumor necrosis factor-alpha, thrombocytocrit) and pulmonary function indicators (peak airway pressure, airway resistance, work of breathing, dynamic compliance) were observed and compared. The results revealed notably less time of hospitalization, pulmonary infection control and fever resolution, as well as a statistically higher bacterial clearance rate in research group vs. control group. After treatment, peak airway pressure, airway resistance and work of breathing were lower while dynamic compliance was higher in research group compared with control group; interleukin-6, high-sensitivity C-reactive protein and thrombocytocrit were lower in research group; and the total clinical effective rate was noticeably higher in research group compared with control group (93.07 % vs. 75.00 %). No evident difference was observed in total adverse reactions between the two cohorts. Therefore, this paper argues that Cefoperazone/Sulbactam plus Azithromycin is beneficial to alleviate inflammation and improve the pulmonary function in patients with severe lower respiratory tract infection, which is worth popularizing.