In an attempt to obtain new candidates with potential anti-inflammatory activity, two series of 1,3,4-oxadiazole based derivatives (8a–g) and 1,2,4-triazole based derivatives (10a,b and 11a–g) were synthesized and evaluated for their COX-1/COX-2 inhibitory activity. In vitro assays showed potent COX-2 inhibitory activity and selectivity of the novel designed compounds (IC50 = 0.04 – 0.16 μM, SI = 60.71 – 337.5) compared to celecoxib (IC50 = 0.045 μM, SI = 326.67). The anti-inflammatory and antioxidant activity of the synthesized compounds was investigated via testing their ability to inhibit pro-inflammatory [tumour necrosis factor (TNF-α) and interleukin- 6 (IL-6)] and oxidative stress [nitric oxide (NO) and reactive oxygen species (ROS)] markers production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Most of the novel compounds exhibited potent anti-inflammatory and antioxidant activity. In particular, the novel compounds showed excellent IL-6 inhibitory activity (IC50 = 0.96 – 11.14 μM) when compared to celecoxib (IC50 = 13.04 μM) and diclofenac sodium (IC50 = 22.97 μM). Moreover, the most potent and selective COX-2 inhibitor 11c (IC50 = 0.04 μM, SI = 337.5) displayed significantly higher activity against NO and ROS production compared to celecoxib (IC50 = 2.60 and 3.01 μM vs. 16.47 and 14.30 μM, respectively). Molecular modelling studies of the novel designed molecules into COX-2 active sites analysed their binding affinity. In-silico simulation studies indicated their acceptable physicochemical properties and pharmacokinetic profiles. This study suggests that the novel synthesized COX-2 inhibitors exert potent anti-inflammatory and antioxidant activity, highlighting their potential as promising therapeutic agents for the treatment of inflammation and oxidative stress-related diseases.