A hybrid pharmacophore approach is used to design and synthesize two novel series of 2′-hydroxychalcone-triazole hybrid molecules 6a-j and 8a-j. These compounds were fully characterized by spectral and elemental analyses. They were evaluated in vitro and in vivo for anti-inflammatory activity. Most of compounds were selective inhibitors for COX-2. Among them, compounds 6d, 6f, 6i, 8c, 8e and 8h demonstrated highly potent dual inhibition of COX-2 (IC50 = 0.037–0.041 µM) and 15-LOX (IC50 = 1.41–1.80 µM). Compounds 6i, 8c and 8h showed 116%, 113% and 109% of the in vivo anti-inflammatory activity of celecoxib. Therefore, compounds 6d, 6f, 6i, 8c, 8e and 8h-j are potent dual inhibitors of COX-2 and 15-LOX. Docking study over COX-2 and 15- LOX active sites ensures the binding affinity and selectivity. These compounds are promising candidates for further development as anti-inflammatory drugs.