Nineteen novel piperine based triazoles have been synthesized using click chemistry approach and were tested for in vivo anti-inflammatory activity. The most active compounds were evaluated for in vitro TNF-α expression. Compounds 3g and 3f were found to show significant in vivo inhibition of inflammation, 80.40% and 76.71%, respectively after 5 h in comparison to piperine (54.72%) and the standard drug indomethacin (77.02%) without causing any damage to the stomach. Compounds 3g and 3f suppressed TNF-α level by 73.73% and 70.64%, respectively and protein expression of COX-2, NF-κB and TNF-α more than indomethacin. Moreover, the compound 3g was found to show significant analgesic activity of 54.09% which was comparable with the indomethacin (57.43%).