Asian ginseng is used as a treatment for cardiovascular diseases, ischemia, and cancers. High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. However, the effect of ginsenosides from Asian ginseng on HMGB1-induced inflammatory responses has not been studied. We addressed this question by monitoring the effects of ginsenoside treatment on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1, and HMGB1-mediated regulation of proinflammatory responses. Ginsenoside treatment suppressed LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. Ginsenosides also inhibited HMGB1-mediated inflammatory responses. In addition, ginsenosides inhibited the production of tumor necrosis factor-${alpha}$ (TNF-${alpha}$) and activation of protein kinase B (Akt), nuclear factor-${kappa}B$ (NF-${kappa}B$), and extracellular-regulated kinases (ERK) 1/2 by HMGB1. Ginsenosides also decreased CLP-induced release of HMGB1, production of interleukin (IL) $1{eta}/6$, and mortality. These results suggested that ginsenosides may be potential therapeutic agents for treatment of vascular inflammatory diseases through inhibition of the HMGB1 signaling pathway.