Objective: To investigate the relationship between serum Serine protease inhibitor A3 (Serpina3) levels, Intravenous immunoglobulin (IVIG) responsiveness, and oxidative stress in children with Kawasaki disease (KD). Methods: This study enrolled 181 KD patients treated between January 2023 and December 2024. According to the IVIG treatment response, they were divided into a IVIG-responsive group (n=154) and an IVIG-resistant group (n=27). Generalized linear mixed models (GLMMs) were used to analyze associations between Serpina3, oxidative stress markers, and IVIG resistance. Receiver operating characteristic (ROC) curves evaluated predictive value, restricted cubic spline (RCS) analysis assessed dose-response relationships, and Bootstrap mediation analysis examined oxidative stress’s mediating role. Results: The IVIG-responsive group showed significantly higher SOD and GSH-Px levels but lower Serpina3 and MDA levels compared to the resistant group (P<0.05). GLMMs revealed that elevated Serpina3 and MDA levels, as well as reduced SOD and GSH-Px levels, increased IVIG resistance risk (P<0.05). RCS analysis demonstrated nonlinear dose-response relationships between these markers and IVIG resistance. Mediation analysis indicated that Serpina3 directly predicted IVIG resistance while exerting an indirect effect through oxidative stress. Conclusion: Serum Serpina3 may serve as a potential biomarker for predicting IVIG treatment response and influence therapeutic sensitivity by modulating oxidative stress pathways, offering novel insights for clinical intervention strategies.