Oridonin, an active diterpenoid compound isolated from the plant Rabdosia Rrubescens, has various pharmacological activities, including antioxidant, anti-tumor capacities and anti-inflammation. In the present study, we explore the role of oridonin in regulating endothelial inflammation and its underlying mechanism. Endothelial cell-monocyte interaction was detected by Leukocyte-endothelium Adhesion Assay. The protein expression was measured by Western blot. NF-κB p65 translocation was measured by immunofluorescence. Acute lung inflammation model was used to evaluate leukocyte infiltration in vivo. The endothelial-leukocyte adhesion and the leukocyte transmigration were profoundly reduced by oridonin. Oridonin dramatically inhibited the expression of TNF-α-induced endothelial adhesion molecules (intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1) and E-selectin) and the pro-inflammatory cytokine (IL-6, IL-8 and monocyte chemoattractant protein-1(MCP-1)). Oridonin suppressed the penetration of the leukocyte in the acute lung injury mice model. Furthermore, Oridonin also suppressed the TNF-α-activated MAPK and Nuclear factor kappa B (NF-κB) activation. Our results suggest that oridonin has the anti-inflammatory properties in endothelial cells, at least in part, through the suppression of MAPK and NF-κB activation, which may have a potential therapeutic use for inflammatory vascular diseases.