<p>In this study, we report a rational molecular design strategy that significantly enhances antioxidant activity by incorporating the propargyl moiety. As proof of concept, we synthesized some substituted aromatic propargyl urea derivatives that possess antioxidant properties via nucleophilic addition reaction. The obtained compounds were fully characterized through various spectroscopic tools, in addition to elemental analysis. Their oxidative stress inhibition potential was evaluated through their ability to scavenge the DPPH radical, where they demonstrated notable free radical inhibition percentages approaching that of vitamin E. Moreover, their IC₅₀ values were assigned and the results revealed very good antioxidant potential for all the synthesized compounds, the values varied with respect to the substituent on the aromatic ring. The overall good antioxidant activities of the products suggests that the propargyl urea moiety serves as a critical pharmacophore for antioxidant activity for the reported molecules. To provide insights into the molecular determinants of the oxidative process from a mechanistic and energetic perspective, a comprehensive DFT investigation has been conducted. This includes frontier molecular orbitals analysis, MEP, and reactivity descriptors. Furthermore, a concise estimation of the bond&#xa0;dissociation&#xa0;energy was performed as a criterion for the stability of the generated free radicals. Notably, the propargylic proton was identified as the most labile proton. Computational studies strongly supported the experimental findings which does not only validates our design concept but also depicts a precise mechanism of action, positioning propargyl-functionalized urea derivatives as a promising platform for advanced antioxidant development.</p> Graphical abstract <p></p>