A series of pyridazinone derivatives, bearing an aryl or pyridyl moiety linked through an ethenyl spacer to position-6 was designed and synthesized. The newly synthesized compounds were screened for preferential inhibition of COX-2 over COX-1 isoforms. Compounds 2c, 2d, 2e, 2f, 3a, 3b, 3c, 3d and 3e are highly potent COX-2 inhibitors with IC50 values in nano-molar range. Moreover, they showed clear preferential COX-2 over COX-1 inhibition with selective indices (SIs) ranging from 4 to 38. Of particular interest, compounds 2d, 2f, 3c and 3d exhibited the most prominent COX-2 inhibitory activity with IC50 values range of 15.56-19.77 nM. They showed SIs of 24, 38, 35 and 24, respectively which were 1.4-2.2 fold higher than celecoxib (SI 17). These four compounds were further investigated in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema method and ulcerogenic liability. Compounds 2f, 3c and 3d demonstrated superior anti-inflammatory activity relative to both indomethacin and celecoxib. None of these compounds showed gastric ulcerogenic effect. On the other hand, compound 2d was found equipotent to celecoxib at the second hour of oral administration. At the fourth hour, it exhibited more potent anti-inflammatory activity than celecoxib, becoming equipotent to indomethacin. It showed mild hyperemia in vivo compared to indomethacin and celecoxib. The molecular docking study of compounds 2d, 2f, 3c and 3d into COX-2 active site revealed a similar binding mode to celecoxib, explaining their remarkable COX-2 inhibitory activity. Taken together, these results indicated that these derivatives are good leads for potential COX-2 inhibitors to be used as potent and safe anti-inflammatory agents.