BACKGROUND: Kawasaki disease (KD) is a pediatric vasculitis that can lead to coronary artery complications if not promptly diagnosed. Its nonspecific early symptoms, primarily fever, often result in misdiagnosis. This study aimed to identify potential biomarkers for early KD diagnosis using proteomic analysis of blood samples. METHODS: Serum samples were collected from three groups: children with acute KD (n = 20, CQB group), age-matched febrile children with bacterial infections (n = 20, C group), and children recovered from KD (n = 8, CQBC group). Proteomic analysis was performed to identify differentially expressed proteins in serum specimens, followed by functional and pathway enrichment analysis. RESULTS: Compared to controls, 92 proteins were upregulated and 101 were downregulated in acute KD, with significant enrichment in the AMPK pathway. In recovered KD, 537 proteins were upregulated and 231 downregulated, predominantly affecting the PI3K-Akt pathway. A total of 56 proteins showed contrasting expression patterns between acute and recovery phases, implicating the complement and coagulation cascades. Notably, complement component 6 (C6), complement component 3 (C3), and α1-antitrypsin (A1AT) emerged as potential biomarkers involved in KD progression and recovery. CONCLUSIONS: C6, C3, and A1AT may serve as novel biomarkers for early KD diagnosis and monitoring. These findings provide new insights into KD pathogenesis and potential targets for clinical application.