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 methylene-tethered linkage among the sesquiterpene scaffolds. Besides the unique linkage of 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 revolving Alder-ene reaction, [3 + 2] cycloaddition, and Michael addition reaction were proposed. Tricarabrols A and B (1 and 2) significantly inhibited nitric oxide production on lipopolysaccaride-stimulated RAW264.7 macrophages, with IC50 values of 2.90 ± 0.05 and 4.52 ± 0.02 μM, respectively, which was comparable with the positive control indomethacin. Further studis indicated that the anti-inflammatory effect of tricarabrol A was mediated through inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB.