Conventional medical therapy of inflammatory diseases relies on the use of non-steroidal anti-inflammatory drugs that reduce fever, pain, and other symptoms of inflammation. The mechanism of action of these drugs involves inhibition of cyclooxygenase (COX) enzymes, which mediate prostaglandin synthesis. However, severe adverse effects, particularly on the gastrointestinal tract, highlight the need for safer gastroprotective agents that selectively suppress inflammatory cytokine production. The aim of the study was to evaluate the binding affinities of five novel oxaprozin derivatives and the reference drug against the COX-1 and COX-2 isoenzymes. Ligand conformer data were generated using OMEGA, while molecular docking was performed using the OEDocking software, employing the FRED algorithm for fast exhaustive rigid docking. Docking results revealed that in the COX-1 active site, compounds 2 and 4 showed the lowest docking scores, comparable to oxaprozin (positive control), while compound 5 exhibited considerably higher values. Compounds 1 and 2 demonstrate similar behavior n the COX-2 binding pocket, forming a conventional hydrogen interaction with Ser353, π-cation electrostatic interaction with Arg120, several hydrophobic interactions with Val349, Leu352, Leu359, Val523, and Ala527. In addition, compound 2 establishes conventional hydrogen bonds with His90 and Arg513, further stabilizing the enzyme-ligand complex and likely accounts for its more favorable docking score compared to oxaprozin.