Macrolides and corticosteroid resistant have been reported in mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult even by sensitive antibiotics in severe MPP (SMPP). SMPP children might develop into airway remodeling even bronchiolitis/bronchitis obliterans. There is an urgent need to identify serum biomarkers indicating the progress of MPP and to discover new target drugs for the treatment of SMPP. In this study, we collected serum samples from general MPP (GMPP) and SMPP patients to perform proteomics profiling. Total 130 differentially expressed proteins with 61 up-regulated in GMPP and 69 up-regulated in SMPP were identified. Among these, FCGBP was one of the most altered protein with highest fold change. Biological enrichment analysis indicated an uncontrolled inflammation catastrophe in SMPP. In addition, complement, coagulation cascades, collagen-containing extracellular matrix and platelet degranulation pathway were enriched in both groups. KEGG analysis indicated an enriched platelet activation in SMPP. ELISA was then performed to verify the dynamic serum FCGBP expression level between other GMPP and SMPP patients. FCGBP level in SMPP was significantly higher than that in GMPP. FCGBP level in GMPP exhibited a decreased trend while SMPP showed the opposite trend during the disease course. Our study demonstrates the first proteomics characteristic of GMPP and SMPP and provides FCGBP as a new serum biomarker indicating the progress of SMPP. Further CMap analysis identified 25 drugs target for the treatment of SMPP. Among them, MTOR inhibitor, a macrolide compound and cell proliferation inhibitor, is the most promising drug targeting for the treatment of SMPP.