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Phyllanthin, a lignan from Phyllanthus species, has been reported to possess potent immunosuppressive properties on immune cells and on adaptive and innate immune responses in animal models. Herein, we investigated the inhibitory effects of phyllanthin isolated from Phyllanthus amarus on nuclear factor‐kappa B (NF‐κB), mitogen‐activated protein kinase (MAPK), and PI3K‐Akt signal transducing pathways in LPS‐activated U937 cells. The lipopolysaccharide‐stimulated excess production of prostaglandin was significantly suppressed by phyllanthin via the mechanisms linked to the modulatory effects of cyclooxygenase 2 protein and gene expression. Phyllanthin also significantly inhibited the release and mRNA expression of proinflammatory cytokines (interleukin‐1 beta and tumor necrosis factor‐alpha). Phyllanthin also significantly downregulated the phosphorylation of IκBα, NF‐κB (p65), and IKKα/β and …