Treatment of inflammation using NSAIDs is coupled with a risk of severe gastric adverse events. Development of dual COX-2/5-LOX inhibitors turns out to be an imperative area devoted to safer NSAIDs. A series of thiourea, thiazole, and thiazolidene derivatives were synthesized by green synthetic approach and COX-1, COX-2 and 5-LOX inhibition screening resulted in the identification of a potent compound 6l with IC50 of 5.55 µM, 0.09 µM, and 0.38 µM respectively. Compound 6l made significant decrease (60.82%) in the carrageenan-induced edema in male Wistar rats. qRT-PCR analysis and determination of PGE2 and LTB4 in the rat paw tissues indicated that this thiazole based dual inhibitor significantly reduced the expression of COX-2 and 5-LOX genes besides the marked reduction in both PGE2 and LTB4 levels. The gastric safety profiling revealed an enhanced gastrointestinal safety of the compound 6l on histopathological examination. Molecular docking studies at COX-2 and 5-LOX active sites were consistent with biological studies by significant protein-ligand interaction. Besides, results of in-vitro PGE2 and LTB4 studies on RAW 264.7 cells as well as antioxidant studies were parallel to the dual inhibitory activity. The present investigations identify a promising lead having anti-inflammatory potential with an improved gastric safety profile. © 2020 Elsevier Inc.