Background and Purpose: Kawasaki disease (KD) is an acute, self-limiting vasculitis with an elusive etiology and can cause vascular endothelial injury. Exosomes derived from induced pluripotent stem cells (iPS-EXO) can exhibit anti-inflammatory, anti-oxidation, and anti-apoptosis properties. The objective of study is to explore the therapeutic effects of iPS-EXO on KD, and try to illuminate the underlying mechanisms. Experimental Approach: Mouse KD model with coronary arteritis induced by Candida albicans wall water-soluble fraction (CAWS) and human umbilical vein endothelial cell (HUVEC) injury KD model induced by tumor necrosis factor-alpha (TNF-α) were established to assess the anti-inflammatory and anti-apoptotic effects of iPS-EXO on KD. Key Results: In vivo experiments revealed that iPS-EXO could significantly inhibit the CD45-positive leukocyte infiltration, mitigate tissue fibrosis, down-regulate the expressions of inflammatory cytokines and chemokines, and reduce vascular endothelial cell apoptosis around coronary arteries of KD mice. In vitro results showed that iPS-EXO could also effectively inhibit TNF-α induced HUVEC inflammation and apoptosis by down-regulating inflammatory cytokines and chemokines, reducing TUNEL positive and flow cytometry apoptotic cells, and decreasing BAX/BCL-2 levels. However, these effects could be reversed by the AMPK inhibitor compound C (CC) and hsa-miR-1976-KO iPS-EXO. Conclusions and Implications: The further mechanism study based on bioinformatics analysis and western blotting indicated that iPS-EXO may exert anti-inflammatory and anti-apoptosis effects on KD through endogenous hsa-miR-1976 binding to CD40 to activate the AMPK/mTOR/NF-κB pathway, suggesting that iPS-EXO may be a promising therapeutic candidate for KD. KEYWORDS: Kawasaki disease (KD), Exosomes derived from induced pluripotent stem cells (iPS-EXO), Endothelial cells, Apoptosis, Inflammation