Objective: To investigate the clinical efficacy and safety of doxycycline combined with methylprednisolone in the treatment of Mycoplasma pneumoniae pneumonia (MUMPP) in children who are unresponsive to macrolides. Method: A retrospective study was conducted on 282 children with MUMPP from March 2023 to October 2025. According to the secondary treatment plan after 72 hours of initial azithromycin treatment, they were divided into two groups: the SDCC+MP group (n=150) switched to doxycycline combined with methylprednisolone; The PAZM group (n=132) continued to extend the course of azithromycin treatment. Compare the clinical efficacy, symptom recovery related indicators [72 hour fever reduction rate after secondary treatment, lung imaging absorption improvement rate, cough relief time, hospital stay], laboratory indicators [white blood cell count (WBC), neutrophil percentage (NE), procalcitonin (PCT), C-reactive protein (CRP)], and incidence of adverse drug reactions between two groups of children. The clinical total effective rate of the SDCC+MP group (93.33%) was significantly higher than that of the PAZM group (70.45%) (P<0.05); The fever reduction rate and improvement rate of lung imaging absorption after 72 hours of secondary treatment in the SDCC+MP group were significantly higher than those in the PAZM group (P<0.05); The cough relief time and hospitalization time in the SDCC+MP group were significantly shorter than those in the PAZM group (P<0.05); After treatment, WBC, NE, PCT, and CRP in both groups were significantly reduced (P<0.05), and the SDCC+MP group was lower than the PAZM group (P<0.05); The total incidence of adverse reactions in the SDCC+MP group was 16.67% (25/150), while in the PAZM group it was 12.12% (16/132), with no statistically significant difference (P>0.05). Conclusion: The clinical efficacy of doxycycline combined with methylprednisolone in the treatment of children with MUMPP is better than that of prolonged azithromycin. It can significantly shorten the time of fever and cough, promote the absorption of lung inflammation, and has good short-term safety. It is worthy of clinical promotion and application.