Due to the association of inflammatory, cancerous, and neurological illnesses with COX-2 overexpression, targeting of this enzyme has become a potent tool for therapeutic research. In the current research, synthesis of novel, straightforward benzimidazole derivatives was described that were selective COX-2 inhibitors and exhibit a striking in vivo anti-inflammatory activity. The most active candidates were five novel molecules 4a, 4b, 5, 6 and 9 showing promising selectivity and in vitro COX-2 inhibition with IC50 of 0.23, 0.27, 0.24, 0.13, and 0.15 µM respectively in comparison with indomethacin IC50 of 0.41 µM. Additionally, using a carrageenan-induced paw edema method, the anti-inflammatory effectiveness of molecules 4a, 4b, 5, 6, and 9 was assessed in vivo. Results revealed that the synthesized compounds had significant inhibitory potency with action like that of the common drug indomethacin. Finally, to comprehend their way of binding, these substances were docked in the crystal structure of the COX-2 enzyme (PDB ID: 4COX). These discoveries may lead to the creation of novel COX-2 inhibitors with enhanced selectivity.