This study aimed to assess macrolide resistance and the genotype distribution of Mycoplasma pneumoniae (MP) in children and identify the risk factors for refractory MP pneumonia (RMPP) during the initial post-COVID-19 outbreak in Wuhu. This retrospective study enrolled children with MPP in Wuhu (November 2023–May 2024). Using preserved nasopharyngeal swabs, macrolide resistance mutations were identified by sequencing the 23S rRNA domain V, and genotyping was performed by PCR. Clinical and laboratory parameters were analyzed to identify the risk factors associated with RMPP. An analysis of 296 pediatric MPP patients revealed universal cough (100%), with high rates of fever (94.93%) and sputum (71.62%). Common findings included moist rales (53.04%) and lobar pneumonia (37.5%). Genotype I (87.84%) predominated and showed a higher A2063G resistance mutation rate than genotype II (74.23% vs 55.56%, P = .019). This mutation was associated with longer hospitalization, more vomiting, and higher C-reactive protein (CRP). RMPP (69.26%) was notable for producing more severe symptoms, higher inflammatory markers (CRP, lactate dehydrogenase [LDH], procalcitonin [PCT], D-D dimer), and a greater need for bronchoscopy and steroid use. Multivariate logistic regression identified prolonged hospitalization, the presence of pulmonary infiltrates, CRP > 10 mg/L, LDH > 246 U/L, and D-D dimer > 0.50 μg/mL as independent risk factors for RMPP. Subsequent receiver operating characteristic curve analysis demonstrated the predictive utility of D-D dimer and LDH levels. The present study established genotype I MP with A2063G-mediated macrolide resistance as the predominant epidemic variant in Wuhu. Independent risk factors for RMPP included a prolonged hospital stay and elevated CRP, LDH and D-D dimer. LDH combined with D-D dimer served as a valuable co-marker for early risk stratification and prediction of refractory disease.