Lung　cancer,　particularly　non-small　cell　lung　cancer　(NSCLC),　remains　a　leading　cause　of　cancer-related　mortality　worldwide.　Resistance　to　epidermal　growth　factor　receptor　tyrosine　kinase　inhibitors　(EGFR-TKIs)　and　the　role　of　epigenetic　modifications,　such　as　histone　deacetylation,　in　cancer　progression　underscore　the　need　for　novel　therapeutic　strategies.　This　study　reports　the　design,　synthesis,　and　biological　evaluation　of　novel　4-arylaminoquinoline　derivatives　as　dual　inhibitors　targeting　EGFR　and　histone　deacetylase　(HDAC).　Leveraging　structureactivity　relationship　insights,　a　series　of　compounds　were　synthesized　by　integrating　pharmacophoric　elements　of　EGFR-TKIs　and　HDAC　inhibitors　and　their　kinase　and　cellular　activities　were　evaluated.　Compound　22c2　exhibited　the　highest　inhibitory　activities　against　EGFR　(IC50　=　4.81　nM)　and　HDAC　(IC50　=　119.4　nM　and　354.8　nM　for　HDAC1　and　HDAC3,　respectively).　Moreover,　22c2　demonstrated　excellent　anti-proliferative　effects　on　four　human　cancer　cell　lines.　These　findings　provide　a　foundation　for　developing　dual　EGFR/HDAC　inhibitors　as　potential　anticancer　therapeutics.