The roots of Angelica tenuissima have been commonly used for the treatment of cardiovascular diseases and menstrual discomfort in Asian countries, such as China and Korea. The primary volatile flavor components are essential oil ingredients, phthalide lactones. In this study, (Z)-ligustilide was tested for its anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that (Z)-ligustilide strongly inhibitis the induction of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the mRNA and protein levels in a dose-dependent manner. The transcriptional activity of nuclear factor kappa B (NF-κB) was also down-regulated in a concentration-dependent manner. Further study revealed that (Z)-ligustilide inhibited the phosphorylation and subsequent degradation of IκBα, an inhibitor protein of NF-κB. In addition, (Z)-ligustilide inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in a dose-dependent manner. Taken together, these data suggest that (Z)-ligustilide can exert its anti-inflammatory effects by regulating the NF-κB and MAPK signal pathways.