Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a risk of serious adverse events. Now, the development of dual inhibitors of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) has become a hot area in searching for safer NSAIDs. NNU-hdpa, 2-(4-hydroxylphenyl)-3-(3,5-dihydroxylphenyl) propenoic acid, a newly synthesized compound, is expected to have COX/5-LOX dual inhibition with an improved gastrointestinal profile. In this study, NNU-hdpa was subjected to in vitro and in vivo experiment protocols. In vitro COX/5-LOX inhibition assays showed that NNU-hdpa exhibits a dual inhibitory activity against the COX and 5-LOX enzymes. Anti-inflammatory activity in vivo was evaluated using two animal edema model tests. Pretreatment with NNU-hdpa (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice and carrageenan-induced paw edema in rats respectively. In gastric lesion test, NNU-hdpa was gastric-sparing in that it elicited markedly fewer stomach lesions as compared to the stomach lesions caused by aspirin in rats. In further studies, NNU-hdpa was found to significantly inhibit the productions of PGE2 and LTB4 in LPS-challenged RAW 264.7, which is parallel to its prevention of the nuclear translocation of the NF-κB p50 and p65 subunits. These data indicate that NNU-hdpa comprises a novel class of dual inhibitors of COX and 5-LOX having therapeutic potential with an enhanced gastric safety profile.