This　work　reports　the　synthesis　of　some　ether-based　hydrazone　derivatives　bearing　commercially　accessible　naproxen　drugs　and　assessed　them　for　their　in　vitro　tyrosinase　inhibitory　activity.　In　the　synthesized　library,　four　derivatives　(7,　12,　8,　and　11)　with　(IC50　=　4.3　±　1.0　to　17.6　±　1.2　µM)　outperformed　kojic　acid　(IC50　=　15.9　±　0.4　µM).　Notably,　compound　(7)　exhibited　∼3.7-fold　improvement　in　inhibitory　potency　over　kojic　acid.　TD-DFT　analysis　correlated　the　observed　activity　with　electronic　properties,　showing　that　compound　(7),　with　its　prop‑2-yn-1-yloxy　substituent,　displayed　the　lowest　energy　gap　(8.124　eV),　highest　electronegativity,　and　electrophilicity.　ADMET　profiling　highlighted　7′s　drug-like　properties　(GI　absorption:　82　%,　hERG　risk:　0.027),　and　favorable　pharmacokinetic　properties,　correlating　with　its　superior　tyrosinase　inhibitory　activity.　Molecular　docking　studies,　using　tyrosinase　(PDB:　5M8Q),　further　elucidated　the　binding　modes,　revealing　strong　hydrogen　bonding　interactions　and　low　binding　energies　for　the　active　compounds,　particularly　compound　(7).　This　combined　computational　and　experimental　approach　will　introduce　a　structurally　innovative　scaffold　with　therapeutic　potential　for　hyperpigmentation　disorders,　guided　by　mechanistic　and　computational　insights.　©　2025　Elsevier　B.V.