Objective：To explore the application value of amoxicillin and clavulanate potassium (AMC) combined with azithromycin (AZM) in children with pneumonia based on changes in serum inflammatory factor levels and symptom improvement. Methods：A retrospective analysis was conducted on the clinical data of 100 children with pneumonia who were admitted to Lu’an People’s Hospital from January 2023 to December 2024, whose etiological results were not definite in the early stage of admission, and who received empirical anti-infective therapy. According to clinical medication regimen, they were divided into the control group (50 cases, treated with AMC) and the observation group (50 cases, treated with AMC combined with AZM). Clinical symptoms, inflammatory levels, lung function, and adverse reactions were compared between the two groups. Results：After 3 d of treatment, the proportions of children with normal body temperature, children without cough, and children without lung rales in the observation group (90.00%, 84.00% and 88.00%) were significantly higher than those in the control group (72.00%, 62.00% and 66.00%) (P<0.05). After treatment, serum levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) in the observation group [(6.41±1.56) pg/mL, (12.64±2.41) pg/mL and (14.36±2.47) pg/mL] were lower than those in the control group [(8.19±1.68) pg/mL, (15.54±2.65) pg/mL and (16.77±2.89) pg/mL] (P<0.05). For lung function, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) in the observation group [(1.85±0.31) L, (2.08±0.38) L and (3.69±0.61) L/s] were higher than those in the control group [(1.62±0.29) L, (1.73±0.36) L and (3.05±0.58) L/s] (P<0.05). The incidence of adverse reactions was 10% in the observation group and 6% in the control group, showing no statistically significant difference (P>0.05). Conclusion：AMC combined with AZM can effectively improve clinical symptoms, reduce inflammatory factor levels, and enhance lung function in children with pneumonia, with good safety.