Herein, the design and synthesis of some novel 1,3,4-trisubstituted pyrazole derivatives was carried out through the structural modification of lonazolac. All the synthesized compounds were investigated for in vitro COX-1 & COX-2 inhibition and in vivo anti-inflammatory activity by a carrageenan rat paw edema model. Among them, the chalcones 2a and 2b were the most COX-2 selective derivatives (S.I. = 8.22 and 9.31, respectively) and revealed very good in vivo anti-inflammatory potency. Similarly, the compounds 4a, 6b, 7a and 8a exhibited good COX-2 selectivity and in vivo anti-inflammatory activity. The active compounds were selected to further investigate their ulcerogenic activity, and they were found to be less ulcerogenic (ulcer indices = 2.4–8.4) as compared to indomethacin (ulcer index = 17.6) and nearly as ulcerogenic as celecoxib (ulcer index = 8.1). Moreover, histological studies were performed to evaluate the safety of these compounds on the stomach, liver and kidney. Furthermore, a docking study was performed to determine possible binding of the most active compounds 2a and 2b, which showed high docking scores (−9.461 and −7.962 kcal mol⁻¹, respectively) that were comparable to that of celecoxib (−8.692 kcal mol⁻¹).