The objective of the study was to develop new Cyclooxygenase-2 inhibitors as anti-inflammatory agents from synthetic route.The 2-phenyl-4H-chromen-4-one and 2-phenyl-2,3-dihydro-4H-chromen-one hybrids were synthesised and characterised by using UV, IR, 1H-NMR, and mass spectrometry. An attempt was made for consolidated the lead flavones and flavanones scaffolds by determining ADME/T properties. Molecular docking simulations were performed by using Autodock.4. for understanding the binding interaction over the targeted enzyme Cyclooxygenase-2. The titled compounds were evaluated for various in-vitro models for antioxidant and anti-inflammatory activities and based upon the IC50 values, the selected compounds were screened for invivo anti-inflammatory activity by both acute and chronic models.The twenty compounds of titled compounds were synthesised and elucidated their structure for confirmation of their functional groups by various spectroscopic techniques. Among the synthesized compounds, in flavone derivatives such as HFc (7-hydroxy-3-(4-methoxy phenyl)-4H-chromen-4-one), HFd (2-(2,4-di methoxy-phenyl)-7-hydroxy-4H-chromen-4-one) and HFe (7-hydroxy-2-(thiophen-2-yl)-4H-chromen-4-one) were produced higher potency. As like, flavanone derivatives HFAc (7-hydroxy-2-(4-hydroxy-3-methoxy phenyl)-2,3-dihydro-4H-chromen-4-one), HFAb (7-hydroxy-2-(4-methoxy phenyl)-2,3-dihydro-4H-chromen-4-one) and HFAd (7-hydroxy-2-(thiophen-2-yl)-2,3-dihydro-4H-chromen-4-one) showed significant anti-inflammatory activity compared to the standard COX-2 inhibitors.The flavone and flavanone scaffolds were posses their excellent inhibitory action over the Cyclooxygenase-2 and acts as a potential anti-inflammatory agents. The results of computational studies were also significantly correlated and conclude that those naturally mimicking flavonoid analogues were tremendous candidates for fighting against the inflammatory diseases in drug discovery.