A novel series of 19 quinoline/1,2,4-triazole hybrid 6a-i and 7a-j was synthesized and evaluated in vitro as dual COX-2/5-LOX inhibitors. Compounds 6e, 6i , and 7e displayed the highest potency and selectivity for inhibiting COX-2 activity (IC 50 = 7.25, 8.13, and 8.48 nM, respectively; selectivity index (COX-1/COX- 2) = 44.89, 30.30, and 33.47, respectively) in comparison to celecoxib (COX-2 IC 50 = 42.60 nM; selectivity index (SI) = 8.05). The anti-inflammatory activity of the newly synthesized compounds was further examined in vivo using a carrageenan induced paw edema assay. Interestingly, the in vitro findings of the COX inhibitory assay were consistent with the in vivo assay. Moreover, 6e, 6i , and 7e showed a substantial reduction in serum concentrations of PGE 2 , TNF- α, IL-6. Molecular docking analysis of compounds 6e , 6 f, 6i, 7e , and 7f revealed high binding affinities toward COX-2 compared to COX-1, which was matched with the experimental results. In addition, these compounds exhibited different binding orientations into the active site of COX-2, which were dependent on the type of substitutions on N4 of the triazole ring. Among the tested derivatives, compounds 6e, 6i and 7e which showed high selectivity to COX-2, exhibited hydrogen bonding interactions with key amino acids in COX-2 such as Arg120, Arg513, and/or Glu524. In addition, the tested compounds also showed multiple hydrogen bonds with the Arg101, Val110, Arg138 or His130 in 5-LOX. These findings show, taken together, that those derivatives are good leads to potential anti-inflammatory agents with lowest gastric damage.