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[Display omitted] • A novel series of imidazoquinazoline-based compounds were designed and synthesized. • Two compounds named 18a and 18o showed noticeable IC 50 values against PC3 and HeLa cell lines. • 18a and 18o demonstrated inhibitory potencies and selectivity toward EGFR (with EGFR-IC 50 values of 82.0 µM and 12.3 µM, respectively). • Western blot analysis of 18a and 18o revealed EGFR and ERK1/2 phosphorylation inhibition. • Computational studies including electrostatic potential map analysis, molecular docking, and non-covalent interaction studies were performed to complete this investigation. Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2- a ]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o , in particular) had great anti-proliferative activities with IC 50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC 50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure–activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations. [ABSTRACT FROM AUTHOR]