The synthesis of novel series of structurally related 4-pyrazolyl benzenesulfonamide derivatives is described. All the newly synthesized compounds were examined for their anti-inflammatory activity using cotton pellet induced granuloma and carrageenan induced rat paw edema bioassays. In addition the inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity were determined. Furthermore, all the compounds were evaluated for their in vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. Docking poses for compounds 6b and 7b separately in the active site of the human COX-2 enzyme and DNA-gyrase B were also obtained. The results revealed that compounds 3c, 4b, 4c, 5c, 6b and 7b exhibited comparable or better anti-inflammatory activity compared to indomethacin and celecoxib with no or minimal ulcerogenic effect and high safety margin. Compounds 3b, 3c, 4b, 4c, 5a-c, 6a, 6b and 7a-c displayed appreciable antibacterial activity against both E. coli and S. aureus compared with ampicillin. Compounds 5a-c and 7a had antibacterial activity against E. coli similar to ampicillin whereas compounds 3b, 3c, 4b, 4c, 6a and 7b displayed considerable activity against the microorganism. Compounds 3a, 3c, 4c, 5a-c, 6b and 7a-c had appreciable activity against S. aureus. Overall, compounds 4c, 6b and 7b are the most distinctive derivatives in the present study because of their remarkable anti-inflammatory potency and significant antibacterial activity. Furthermore, compounds 6b and 7b exhibited good selective inhibitory activity against COX-2 enzyme. Therefore, such compounds would represent a suitable template for the design of anti-inflammatory antimicrobial candidates with reasonable COX-2 selectivity.