Non-steroidal anti-inflammatory drugs (NSAIDs) such as ketorolac (KTR) are widely employed for postoperative analgesia through inhibition of prostaglandin synthesis. However, their clinical use is often limited due to adverse effects, particularly gastrointestinal irritation and ulceration. In this study, structural modifications were introduced by replacing the hydroxyl group of the carboxylic acid moiety of KTR with a range of functional substituents, including –CH3, –OCH3, –CF3, –OCF3, –NH2, –CH2NH2, –NHCOCH3, and –NHCONH2. We conducted a comprehensive in-silico evaluation combining quantum chemical calculations with computer-aided drug design (CADD) protocols to assess the physicochemical, spectral, pharmacological, and toxicological properties of the new analogs. Molecular docking against cyclooxygenase-2 (COX-2) revealed that most KTR derivatives exhibit higher docking score relative to the parent KTR. Further validation via molecular dynamics simulations confirmed the stability of the selected ligand-enzyme complexes. In silico pharmacokinetic profiling (ADMET) predicted generally drug-like characteristics for the designed analogs, with certain differences from the parent compound. PASS (Prediction of Activity Spectra for Substances) analysis predicted that several analogs may retain anti-inflammatory activity. These designed KTR analogs warrant further in-vitro COX-2 inhibition assay to determine the COX-2 inhibitory activity.