Tricarabrols A-C (1-3), three sesquiterpene lactone trimers, were identified from Carpesium faberi. Tricarabrols A and B are a pair of stereoisomers possessing a novel C44 skeleton featuring a methylene-tethered linkage among the sesquiterpene scaffolds. Besides the unique linkage of the cyclopentane ring, tricarabrol C also manifests a methylene bridge. Their full structures were established on the basis of spectroscopic data and further confirmed by computational methods. The biosynthetic pathways involving the Alder-ene reaction, [3 + 2] cycloaddition, and Michael addition reaction were proposed. Tricarabrols A and B (1-2) significantly inhibited the nitric oxide production on lipopolysaccaride-stimulated RAW264.7 macrophages with IC50 values of 2.90 and 4.52 μM, respectively, compared with the positive control indomethacin. Further studies indicated that the anti-inflammatory effect of tricarabrol A was mediated through inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB.