In continuation of our interest on the synthesis of fused quinoxalines and pyrazines derivatives and due to the resultant pharmacological interest in compounds which belong to these heterocyclic derivatives. In this manuscript, we direct for preparation of some indenoquinoxaline and pyrazine derivatives, with spectral characterization using different spectral techniques including IR, NMR, together with elemental analyses. The newly synthesized derivatives were subjected to cytotoxic screening using the MTT assay against MCF-7 and A549 cell lines. Compounds 6, 8a, 9, 10, and 11 exhibited a potent cytotoxic activity, especially compound 11 with IC50 values 5.4 and 4.3 mM against MCF-7 and A549, respectively. Molecular docking calculations of the tested derivatives exhibited a good binding affinity towards EGFR receptor binding site, which might explain their proposed mode of action.