This study aimed to investigate the effect of erythromycin sequential therapy plus azithromycin on lung function and inflammatory factors in children with severe mycoplasma pneumonia (MP). Ninety-three severe MP children were selected and randomized into azithromycin group, erythromycin group, and combination group, 31 cases in each. The disappearance time of cough, fever, lung rale and X-ray shadow in the combination group were shorter than those in the azithromycin group and erythromycin group. The clinical treatment efficiency of the combination group was higher than that of the azithromycin group. After treatment, FVC, FEV1/FVC and PEF in combination group were higher than before treatment; IL-8, IL-6, CRP in combination group were lower than erythromycin group and azithromycin group. IL-8, IL-6, CRP are negatively correlated with disappearance time of cough, fever, pulmonary rale, X-ray shadow and clinical treatment efficiency; FEV1/FVC is positively correlated with disappearance time of cough and fever, pulmonary rales and X-ray shadow, and clinical treatment efficiency. Sequential erythromycin therapy combined with azithromycin in the treatment of MP can effectively inhibit high inflammatory reactions, control the disease in a timely manner, improve lung function and produce fewer adverse reactions.