A new series of quinazoline-4-one/chalcone hybrids, 7–26 , was synthesized in this study as EGFR in- hibitors with antiproliferative activity. Target compounds were synthesized and in vitro tested against different cancer cell lines, EGFR, and BRAF enzymes. Three compounds showed the greatest antiprolif- erative activity and were the most potent EGFR inhibitors. Also, these three compounds improved the level of active caspase-3, 8, and 9 with potent induction of cytochrome c and Bax levels, as well as down regulation of Bcl - 2 levels. Finally, the most active inhibitors docked well inside EGFR active sites.