A new dibenzylbutyrolactone lignan, (2 R,3 R)-5'-methoxyguayarol (1), was isolated from an EtOAc-soluble extract of the seeds of Hernandia ovigera using an in vitro activity-guided fractionation procedure based on the inhibition of cyclooxygenase-2. Also obtained were three known fatty acid derivatives, (S)-coriolic acid, (+/-)-12,13-epoxyoleic acid, and (+/-)-glycerol 1-monolinolate, and seven known lignans, epiashantin, dehydrodesoxypodophyllotoxin, dehydropodophyllotoxin, (-)-hernolactone, (-)-pinoresinol, (-)-syringaresinol, and (-)-yatein. The structure, including absolute stereochemistry, of compound 1 was determined using spectroscopic methods. All isolates were tested for their inhibitory effects against both cyclooxygenases-1 and -2, with (S)-coriolic acid and (+/-)-glycerol 1-monolinolate shown to have selective inhibitory activity with cyclooxygenase-2.