Abstract <p>This study focused on the design, synthesis, and evaluation of novel quinazoline Schiff bases as potent inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK), with an emphasis on their antiproliferative effect against A549 lung cancer cell line. The compounds were computationally designed and synthesized, and molecular docking studies were conducted to examine their interactions within the EGFR-TK binding pocket. Molecular dynamics simulations were performed to assess the stability and conformational behavior of the hybrids, while Density Functional Theory (DFT) calculations were employed to validate their optimized geometries. Among the synthesized compounds, three analogues demonstrated significant inhibitory activity. In particular, compound <b>6b</b> featuring a <i>p</i>-hydroxyphenyl group showed an IC₅₀ of 1.44±1.07 µg/mL, while compound <b>6f</b> with a 4-fluorophenyl moiety showed an IC₅₀ of 1.58±1.25 µg/mL. and compound <b>6h</b> with a 3,4-dimethoxyphenyl moiety exhibited an IC₅₀ of 1.7±1.32 µg/mL. Erlotinib used as reference drug displayed an IC₅₀ of 7.32±0.52 µg/mL. Molecular modeling identified key structural features contributing to the observed activities. This comprehensive study highlights the potential of quinazoline Schiff bases as promising EGFR-TK inhibitors, offering insights into their structural optimization and interactions for cancer therapy.</p>