Based on the observed pharmacophoric structural features for the reported dual COX/15-LOX inhibitors and inspired by the abundance of COX/LOX inhibitory activities reported for the 1,2,4-triazine and quinoline scaffolds, we designed and synthesized novel 1,2,4-triazine-quinoline hybrids (8a-n). The synthesized hybrids were evaluated in vitro as dual COXs/15-LOX inhibitors. The new triazine-quinoline hybrids (8a-n) exhibited potent COX-2 inhibitory profiles (IC50 ¼ 0.047e0.32 mM, SI ~ 20.6e265.9) compared to celecoxib (IC50 ¼ 0.045 mM, SI ~ 326). Moreover, they revealed potent inhibitory activities against 15-LOX enzyme compared to reference quercetin (IC50 ¼ 1.81e3.60 vs. 3.34 mM). Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor (COX-2 IC50 ¼ 0.047 mM, SI ¼ 265.9, 15-LOX IC50 ¼ 1.81 mM). These hybrids were further challenged by their ability to inhibit NO, ROS, TNF-a, IL-6 inflammatory mediators, and 15-LOX product, 15-HETE, production in LPS-activated RAW 264.7 macrophages cells. Compound 8e was the most potent hybrid in reducing ROS and 15-HETE levels showing IC50 values of 1.02 mM (11-fold more potent than that of celecoxib, IC50 ¼ 11.75 mM) and 0.17 mM (about 43 times more potent than celecoxib, IC50 ¼ 7.46 mM), respectively. Hybrid 8h exhibited an outstanding TNFa inhibition with IC50 value of 0.40 mM which was about 25 times more potent than that of celecoxib and diclofenac (IC50 ¼ 10.69 and 10.27 mM, respectively). Docking study of the synthesized hybrids into the active sites of COX-2 and 15-LOX enzymes ensures their favored binding affinity. To our knowledge, herein we reported the first 1,2,4-triazine-quinoline hybrids as dual COX/15-LOX inhibitors.