This study investigated the molecular mechanisms of immune responses in Kawasaki disease (KD) and COVID-19 using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs). The scRNA-seq analysis revealed differences in immune cell composition and gene expression between KD and COVID-19 patients. While both KD and COVID-19 showed elevated CD14+ monocytes, the activation of adaptive immunity differed between the two diseases. Monocytes in COVID-19 showed adhesion to both endothelial and alveolar epithelial cells, highlighting shared phenotypes. In vitro experiments validated the scRNA-seq findings, showing that SELL+/CCR1+/XAF1+ CD14 monocytes enhanced endothelial cell adhesion and damage.