Objective: To synthesize and preliminary pharmacological evaluation of new analogs of several new Schiff bases of diclofenac by investigating their interactions with COX-2 by docking and defining certain associations between their structures to improve selectivity towards COX-2 and to decrease side effects. Methods: Several new diclofenac Schiff bases were designed, prepared, and tested as potential COX-2 inhibitors. These new compounds were tested by molecular docking using genetic optimization for ligand docking suite for evaluated of their in vivo anti-inflammatory activity and COX-2 selectivity. Results: Because of their hydrogen bonding interaction with main amino acids in COX isozymes Arg121, Tyr356, and Ser120, all compounds evaluated in molecular docking exhibited important activities compared with diclofenac and 4PH9 as comparison drugs. The results of the ADME showed that all synthesized compounds absorbed from GIT while all compounds except (Yr 05 h-j) followed the Lipinski law. Conclusion: The production of the designed compounds has been managed successfully, the anti-inflammatory evaluation of the end products suggests that the new Schiff bases derivatives have strengthened their anti-inflammatory action, docking studies have shown that the preliminary analysis of anti-inflammatory activity has shown that all compounds (Yr 04, Yr 05 a-j) have strong anti-inflammatory properties, excluding Yr 03.