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Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds <b>9</b>–<b>16</b> showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (<i>p</i> < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds <b>9</b> and <b>16</b> bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds <b>9</b> and <b>16</b>. Both compounds demonstrated favorable predicted GI absorption values, while only <b>16</b> was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound <b>16</b> is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds <b>9</b> and <b>16</b>.