Introduction: Mycoplasma Pneumoniae Pneumonia (MPP) is an inflammation of the lungs caused by Mycoplasma pneumoniae infection. Macrolide antibiotics are the therapeutic agents of choice for MPP. This study aimed to explore the efficacy of erythromycin cyclic 11,12-carbonate combined with azithromycin in treating children with severe Mycoplasma pneumoniae pneumonia (SMPP). Methods: 84 children with SMPP treated at Hubei Maternal and Child Health Hospital between February 2021 and December 2021 were randomly divided into two groups. The control group was treated with intravenous azithromycin and then changed to oral azithromycin. The experimental group was treated with intravenous azithromycin and then switched to oral erythromycin cyclic 11,12-carbonate. The clinical efficacy, symptom improvement, inflammatory levels, and cytokine levels before and after treatment were compared, and the occurrence of adverse reactions was recorded. Results: The overall effective rate of treatment in the experimental group was significantly higher than that in the control group (P<0.05). The time to the disappearance of clinical symptoms and length of hospitalization of the experimental group was significantly shorter than that of the control group (P<0.05). After treatment, inflammatory levels and cytokine levels of the experimental group were significantly lower than those of the control group (P<0.05). There was no difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion: Erythromycin cyclic 11,12-carbonate combined with azithromycin in the treatment of children with SMPP had significant efficacy, superior to azithromycin monotherapy, which could effectively improve immune function and clinical symptoms.