Kawasaki Disease (KD) is an acute and self-limiting vasculitis of unknown etiology that mainly occurs in infancy and can lead to vascular endothelial injury. Hesperidin (HES) is an economical dietary biological flavonoid with anti-oxidant, anti-inflammatory, and anti-apoptotic pharmacological effects. The main objective of this study was to investigate the protective effects of HES on KD, and try to elucidate the underlying mechanism. The Candida albicans water-soluble fraction (CAWS) was used to induce coronary arteritis of KD mouse model in vivo, and tumor necrosis factor α (TNF-α) was employed to induce human umbilical vein endothelial cell (HUVEC) injury of KD cell model in vitro to investigate the anti-inflammatory and anti-apoptotic effects of HES on KD. Our in vivo results showed that HES significantly reduced coronary artery injury in KD mice by alleviating pericoronary inflammatory infiltration and tissue fibrosis, inhibiting inflammatory cytokines and chemokine expressions, and decreasing vascular endothelial cell apoptosis. Our in vitro study confirmed that HES had the opposite ability of the NF-κB agonist NF-ĸB activator 1 (ACT1) to significantly alleviate the inflammatory response, CellROX level, and apoptosis by decreasing BAX/BCL-2 and Cleaved Caspase-3 levels as well as reducing TUNEL positive cells and the ratio of flow cytometric apoptotic cells in TNF-α induced HUVECs. The further mechanism study based on bioinformatics analysis and western blotting demonstrated that HES could protect against vascular inflammation and cell apoptosis of KD through inhibiting the TLR4/IĸBα/NF-ĸB pathway, suggesting that HES may be a promising therapeutic candidate for KD.