Cyclooxygenase (COX) enzymes are involved in inflammation and cancer. Nine derivatives of hydroxycinnamic acids including ethyl and diethyl esters were synthesized and tested as COX inhibitors in whole blood assay. Esterification improved COX-1 and COX-2 inhibitory activities of the derivatives. Ethyl esters were more effective against COX-1 and the most potent one was caffeic acid ethyl ester. Interestingly, diethyl esters showed selectivity towards COX-2; The most active compound was caffeic acid diethyl ester (CA-DE) with 88.5 and 30.5% inhibitions against COX-2 at 100 and 20 µM, respectively, while it was almost inactive against COX-1. Docking studies showed that CA-DE forms 3 hydrogen bonds with the active site of COX-2 (4-OH..OH-Tyr355, 4-OH..NH-Arg120 and C=O..OH-Tyr385), while it forms only the first two bonds with COX-1. Furthermore, Val523 residue in COX-2 provides a wide hydrophobic pocket, which would accommodate diethyl esters. The present approach inspired by a natural scaffold provides an asset for the generation of new chemical entities endowed with selective COX-2 inhibitory activity.