Chemokines play important roles in the pathogenesis of asthmatic inflammation. Sesamin, a class of phytoestrogen isolated from sesame seed Sesamum indicum, is recently regarded as an anti-inflammatory agent. However, the effects of sesamin on asthma-related chemokines are unknown. To this end, we investigated the effects of sesamin on the expression interferon-γ-inducible protein-10 (IP-10/CXCL10), macrophage-derived chemokine (MDC/CCL22), growth-related oncogene-α (GRO-α/CXCL1) and tumor necrosis factor (TNF)-α in human monocytes. Cells were pretreated with sesamin before lipopolysaccharide (LPS) stimulation. IP-10, MDC, GRO-α and TNF-α were measured by ELISA. Involved receptors and intracellular signaling were investigated by receptor antagonists, pathway inhibitors, western blotting and chromatin immunoprecipitation. Sesamin suppressed LPS-induced MDC in THP-1 and human primary monocytes. Sesamin suppressed LPS-induced IP-10 in THP-1 cells, but not human primary monocytes. Sesamin had no effects on LPS-induced GRO-α and TNF-α expression in THP-1 and human primary monocytes. The suppressive effect of sesamin on MDC was reversed by the estrogen receptor (ER) and peroxisomal proliferator-activated receptor (PPAR)-α antagonists. Sesamin suppressed LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38 and nuclear factor kappa B (NFκB)-p65. Sesamin suppressed histone H3/H4 acetylation in the MDC promoter region. Sesamin suppressed LPS-induced MDC expression via the ER, the PPAR-α, the MAPK-p38 pathway, the NFκB-p65 pathway and the epigenetic regulation. Sesamin may have therapeutic potential in preventing and treating asthma.