Objective This study aimed to comprehensively compare the clinical characteristics and protein expression differences between refractory mycoplasma pneumoniae pneumonia and ordinary mycoplasma pneumoniae pneumonia in children, summarizing the disease characteristics, causes, and pathogenic mechanisms of mycoplasma pneumoniae pneumonia.Methods A total of 90 clinical records were collected for children with mycoplasma pneumonia admitted to our hospital from December 2021 to December 2024. Based on disease severity and treatment response, the children were divided into a RMPP group (45 cases) and an ordinary group (45 cases). We compared the levels of inflammatory factors (SAA, NLR, PLR, CRP, IFN-γ), coagulation function indicators (D-D, FIB), humoral immune levels (IgG, IgA, IgE, IgM), and the relative expression levels of proteins (TLR4, NF-κB, Keap1, Nrf2, p-p53) between the two groups. Combined with clinical manifestations, the differences in clinical characteristics and pathogenic mechanisms between refractory and ordinary mycoplasma pneumoniae pneumonia in children were investigated. Results There were no significant differences in gender and age between the two groups (P>0.05). The RMPP group had significantly higher levels of serum SAA, CRP, NLR, PLR, IgM, IgE, INF-γ, D-D, and FIB compared to the typical pneumonia group (P<0.05). No significant differences were observed in IgA and IgG levels between the two groups. Additionally, the RMPP group had higher levels of serum IL-6 and IL-12p70 compared to the typical pneumonia group (P<0.05). Conclusion The inflammatory and humoral immune responses in RMPP are more pronounced, primarily in the lungs, which may promote pulmonary inflammation and contribute to the process of pulmonary fibrosis. RMPP patients are more likely to experience changes in the hematological system, leading to various thrombotic diseases, such as pulmonary embolism. Mycoplasma pneumoniae can directly or indirectly affect the host's coagulation system, activating the coagulation cascade and leading to a hypercoagulable state. The pathogenesis of RMPP is associated with the TLR4/NF-κB and Nrf2/p53 pathways, with the Nrf2/p53 pathway being a key distinguishing factor between RMPP and typical Mycoplasma pneumoniae pneumonia