In our effort to identify potent gastric sparing anti-inflammatory agents, a series of methyl sulfanyl/methyl sulfonyl substituted 2,3-diaryl quinazolinones were designed by analogue-based design strategy and synthesized for biological evaluation. Subsequently, the compounds were evaluated for both cyclooxygenase inhibitions by ovine COX assay and carrageenan-induced rat paw edema assay. All the methyl sulfonyl substituted quinazolinones were exhibited promising anti-inflammatory activity. In particular, 6-bromo-3-(4-methanesulfonyl-phenyl)-2-phenyl-3H-quinazolin-4-one, 7-chloro-3-(4-methanesulfonyl-phenyl)-2-phenyl-3H-quinazolin-4-one, 3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-3H-quinazolin-4-one and 6-bromo-3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-3H-quinazolin-4-one emerged as the most active compounds in the series. The results of ulcerogenic activity assay suggest that these compounds are gastric safe compared to indomethacin. The molecular docking analysis was performed to understand the binding interactions of these compounds to COX-2 enzyme. The results from the present investigation suggests that 2,3-diaryl quinazolinones as a promising template for the design of new gastric safe anti-inflammatory agents, which can be further explored for potential anti-inflammatory activity.