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Background Kawasaki Disease (KD), which is mainly characterized by systemic small and medium vasculitis in children, can lead to coronary artery lesions (CALs). Our previous study identified that STAT3 signaling plays essential roles during the acute phase of KD patients. However, whether its interacted protein MDM2 (Murine double minute 2), which functions as an E3 ligase is likewise involved in KD pathogenesis still unknown and remains to be investigated. Methods The role of MDM2 was investigated using the whole-blood samples from KD patients with CALs before and after IVIG treatment. The plasma and peripheral blood mononuclear cells were respectively isolated and collected. Meanwhile, a Candida albicans cell wall extracts (CAWS)‑induced KD mouse model was used to analyze the in vivo functions of MDM2. Real-time PCR, western blotting, and enzyme-linked immunosorbent methods were used respectively in the HCAECs or other cells to investigate the molecular mechanism of MDM2 involved in KD. Results MDM2 levels were downregulated, and STAT3 and VEGFA levels were upregulated in clinical blood samples from KD patients with CAL in the acute stage and in the mouse model. In the mouse model and HCAECs, MDM2 co-located with STAT3 . In vitro, the endogenous STAT3 protein level in HCAECs was upregulated after MDM2knockdown. Overexpression of MDM2 increased STAT3 ubiquitination and endogenous STAT3 and VEGFA levels decreased significantly. Additionally, the E3 ubiquitin ligase MDM2 can target its endogenous substrate STAT3 for ubiquitination. Conclusions Decreased MDM2 levels can reduce STAT3 ubiquitination, leading to STAT3 activation and the induction of VEGFA transcription, which is involved in the vascular endothelial inflammatory injury process of KD.