<jats:p>Torilin, a sesquiterpene isolated from the fruits of<jats:italic>Torilis japonica,</jats:italic>has shown antimicrobial, anticancer, and anti-inflammatory properties. However, data on the mechanism of torilin action against inflammation is limited. This study aimed at determining the anti-inflammatory property of torilin in LPS-induced inflammation using in vitro model of inflammation. We examined torilin’s effect on expression levels of inflammatory mediators and cytokines in LPS-stimulated RAW 264.7 macrophages. The involvement of NF-kB and AP-1, MAP kinases, and adaptor proteins were assessed. Torilin strongly inhibited LPS-induced NO release, iNOS, PGE<jats:sub>2</jats:sub>, COX-2, NF-<jats:italic>α</jats:italic>, IL-1<jats:italic>β</jats:italic>, IL-6, and GM-CSF gene and protein expressions. In addition, MAPKs were also suppressed by torilin pretreatment. Involvement of ERK1/2,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant="normal">P</mml:mi><mml:mn mathvariant="normal">38</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant="normal">M</mml:mi><mml:mi mathvariant="normal">A</mml:mi><mml:mi mathvariant="normal">P</mml:mi><mml:mi mathvariant="normal">K</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math>, and JNK1/2 was further confirmed by PD98059, SB203580, and SP600125 mediated suppression of iNOS and COX-2 proteins. Furthermore, torilin attenuated NF-kB and AP-1 translocation, DNA binding, and reporter gene transcription. Interestingly, torilin inhibited TAK1 kinase activation with the subsequent suppression of MAPK-mediated JNK, p38, ERK1/2, and AP-1 (ATF-2 and c-jun) activation and IKK-mediated I-<jats:italic>κ</jats:italic>B<jats:italic>α</jats:italic>degradation, p65/p50 activation, and translocation. Together, the results revealed the suppression of NF-<jats:italic>κ</jats:italic>B and AP-1 regulated inflammatory mediator and cytokine expressions, suggesting the test compound’s potential as a candidate anti-inflammatory agent.