Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC<sub>50</sub> = 0.140, 0.007 μm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.