In view of their expected anti-inflammatory activity, novel series of 6-iodo-2-phenyl-quinazolin-4(3H)-one (4-12_a-d) were designed and synthesized in order to evaluate their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Most of the novel quinazolinone derivatives showed considerable potent anti-inflammatory activities of superior G.I.T. safety profile in experimental rats in comparing to indomethacin as a reference drug. The molecular docking was performed for all synthesized compounds to assess their binding affinity to COX-2 enzyme in order to rationalize their anti-inflammatory activity in a qualitative way. The obtained data from the molecular modeling was strongly correlated with that obtained from the biological screening. The highest binding affinities were noticed for compounds 8_a, 12_b and 10_b which showed the highest anti-inflammatory activities of this series. Compounds 12_b, 9_c and 8_a exhibited the least ulcerogenic effect in all of the experimental animals.