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 <i>in vitro</i> COX-1 & COX-2 inhibition and <i>in vivo</i> anti-inflammatory activity by a carrageenan rat paw edema model. Among them, the chalcones <b>2a</b> and <b>2b</b> were the most COX-2 selective derivatives (S.I. = 8.22 and 9.31, respectively) and revealed very good <i>in vivo</i> anti-inflammatory potency. Similarly, the compounds <b>4a</b>, <b>6b</b>, <b>7a</b> and <b>8a</b> exhibited good COX-2 selectivity and <i>in vivo</i> 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 <b>2a</b> and <b>2b</b>, which showed high docking scores (-9.461 and -7.962 kcal mol<sup>-1</sup>, respectively) that were comparable to that of celecoxib (-8.692 kcal mol<sup>-1</sup>).