Objective: To explore the effect of combination of doxycycline and budesonide atomization in the treatment of drug-resistant mycoplasma pneumonia in children. Methods: Eighty children with macrolide-resistant Mycoplasma pneumoniae pneumonia admitted from January 2024 to June 2024 were selected and grouped according to different medication regimens. 38 cases in the control group were treated with azithromycin combined with budesonide atomization therapy, and 42 cases in the study group were given doxycycline combined with budesonide atomization therapy. The clinical efficacy, symptom improvement status, inflammatory indicators and adverse reactions were compared between the two groups. Results: The effective rate of clinical treatment in study group was 97.62%, which was significantly higher than 81.58% in control group (P<0.05). The fever abatement time, cough relief time and lung rale disappearance in study group were significantly shorter than those in control group (P<0.05). After treatment, the levels of C-reactive Protein, Interleukin-6 and Interleukin-8 in the two groups were decreased, and the levels in study group were significantly lower (P<0.05). During treatment, there was no significant difference in the total incidence rate of adverse reactions between groups (P>0.05). Conclusion: Doxycycline combined with budesonide atomization therapy has exact efficacy on macrolide-resistant Mycoplasma pneumoniae pneumonia in children.