Natural products have been used as potentially important sources of anti-inflammatory drugs. This study examined the effects of pinocembrin against lipopolysaccharide (LPS)-induced endotoxemia to ascertain whether pinocembrin could protect mice from ensuing death. Cytokine responses were also assessed in serum isolated from blood collected at 0, 2, 4, 6, 8, and 24 h after LPS administration of the mice (with or without drug treatment). The results showed that there was a lower production of TNFα, IL-6, and IL-1β in the serum of LPS-challenged mice that had been pre-treated with pinocembrin. In addition, pre-treatment with pinocembrin improved host survival against the LPS-induced lethal endotoxemia. These results suggest that this new flavonoid could potentially be a novel candidate for preventing development/mitigation progression of septic shock.