Naproxen (NAP) is one of the commonly used nonselective Cycloxygenase (COX) inhibitors. It is a choice of drug for anti-inflammatory activity by subsiding the generation of the inflammatory components called prostaglandins. The common problem associated with the NAP is gastrointestinal toxicity. It may cause ulceration or stomach bleeding. In this study, the different derivatives of NAP were designed by using phytophenols with the aim that they exert the antioxidant activity and have the potential to reduce ulcer formation. The lead molecules were designed by molecular docking-based virtual screening against human COX-2 enzyme through AutoDock. Then these derivatives were screened for pharmacokinetic profiling by considering Lipinski's filter. The potent and safe molecule was identified by pharmacokinetics and toxicity evaluation. The potent compound was synthesized in the laboratory, purified, characterized, and its pharmacological activities were evaluated. The resultant compound was found to be equipotent and less toxic than the parent compound.