A new sesquiterpene lactone was isolated from Siegesbeckia glabrescens as an inhibitor of nitric oxide and prostaglandin E2 synthesis in the LPS-activated RAW264.7 macrophage cell line. It dose-dependently decreased the protein and mRNA levels of inducible nitric oxide synthase and cyclooxygenase-2. Reporter gene assay revealed that the compound attenuated the LPS-induced DNA transcriptional activity of nuclear factor-kappa B (NF-κB). In addition, it inhibited the nuclear translocation of the p65 subunit of NF-κB by blocking the inhibitory kappa B-α degradation. This compound from Siegesbeckia glabrescens might be beneficial for the treatment of inflammation-related diseases.