One of the helpful ways to improve the effectiveness of anticancer agents and weaken drug resistance is to use hybrid molecules. therefore, the current study intended to introduce 20 novel xanthine/chalcone hybrids 9-28 of promising anticancer activity. Compounds 101113141620 and 23exhibited potent inhibition of cancer cells growth with IC50 ranging from 1.0±0.1 to 3.5±0.4 μM compared to doxorubicin with IC50 ranging from 0.90± 0.62 to 1.41 ± 0.58 μM and that compounds 11 and 16 were the best. To verify the mechanism of their anticancer activity, compounds 101113141620and 23 were evaluated for their EGFR inhibitory effect. The study results revealed that compound 11 showed IC50 = 0.3 µM on the target enzyme which is more potent than staurosporine reference drug (IC50 = 0.4 µM). Accordingly, the apoptotic effect of the most potent compounds 11 was extensively investigated and showed a marked increase in Bax level up to 29 folds, and down-regulation in Bcl2 to 0.28 fold, in comparison to the control. Furthermore, the effect of compound 11 on Caspases 3 and 8 was evaluated and was found to increase their levels by 8 and 14 folds, respectively. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking study was adopted to confirm mechanism of action.