Macrophages-mediated inflammation is involved in the regulation of Rheumatoid arthritis (RA) [1]. Sigesbeckiae Herba (SH) has been traditionally used for rheumatism [2]. Recently, we isolated a sesquiterpenoid compound (Leocarpinolide B, LB) from SH and identified its anti-inflammatory and antioxidant effects on RAW264.7 macrophages for the first time. LB effectively inhibited excessive nitric oxide (NO) production and cytokines secretion (IL-6, TNF- -1), and the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthases (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 cells. LB also blocked the activation of nuclear factor kappa B (NF-kB) failed to inhibit the activation of NLRP3 inflammasome. Additionally, LB reduced the intracellular reactive oxidative oxygen (ROS), and increased the expression of heme oxygenase-1 (HO-1) and the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the presence or absence of LPS treatment. The results suggested that LB might be a promising candidate for the treatment of inflammation-related diseases and valuable to be further investigated. Summary diagram shows that LB attenuates LPS-induced inflammation on RAW264.7 macrophages by mediating NF-kB and Nrf2 pathways. Red arrow represents LPS-induced changes whereas green arrow shows the effects of LB.