The essential oils from Rimulus cinnamon (EORC) have anti-inflammation activities, but the effects of EORC on endotoxin poisoning mice remain to be explored, the mechanism is still unclear. This study was designed to investigate the protective effects and mechanism of EORC on lipopolysaccharide (LPS)-induced endotoxin poisoning mice. Pre-treatment with EORC decreased the production of pro-inflammatory cytokines (Interleukin-1β, Interleukin-18, Interleukin-5, and Interferon-γ) and chemokines (Monocyte chemotactic protein-1, Macrophage colony-stimulating factor, and Macrophage inflammatory protein-1β) in serum of endotoxin poisoning mice. The histopathological study showed that the lung injury was improved and EORC decreased the numbers of neutrophils and Nitric oxide (NO) levels in lung. EORC could reduce the mRNA expression of NLR family, pyrin domain-containing 3 (NLRP3), Interleukin (IL)-1β, and nitric oxide synthase (iNOS). In addition, EORC decreased the protein expression of NLRP3, Caspase-1 (p20), Pro-IL-1β, and purinergic P2 × 7 receptor (P2 × 7R) in the lung tissues. The results above indicated that the EORC may have protective effects on LPS-induced endotoxin poisoning mice via inhibiting the activation of P2 × 7R/NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]