Objective: To evaluate the efficacy and safety of doxycycline and azithromycin in the treatment of macrolide-resistant Mycoplasma pneumoniae pneumonia in children. Methods: 100 pediatric patients with Mycoplasma pneumoniae pneumonia treated with azithromycin or doxycycline were selected as the study subjects. After propensity score matching, 34 patients received azithromycin and were assigned to the azithromycin group, while 34 patients received doxycycline and were assigned to the doxycycline group. Data on the children's general characteristics, time to fever resolution, time to cough resolution, duration of pulmonary findings, C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer levels, and adverse events observed during treatment were collected from electronic medical records. Results: In the doxycycline group, pulmonary findings, time to cough resolution, and time to fever resolution were all shorter than those in the azithromycin group, with statistically significant differences (P<0.05). After treatment, the levels of CRP, D-dimer, and LDH in children from both groups were lower than before treatment, and those in the doxycycline group were lower than those in the azithromycin group, with statistically significant differences (P<0.05). There was no statistically significant difference in the incidence of adverse events (rash and gastrointestinal symptoms) between the doxycycline and azithromycin groups after treatment (P>0.05). Conclusion: Doxycycline treatment for macrolide-resistant Mycoplasma pneumoniae pneumonia in children can accelerate the resolution of clinical symptoms and reduce LDH, CRP, and D-dimer levels, with superior efficacy compared to azithromycin.