New series of 5-(morpholinosulfonyl) isatin derivatives were designed and synthesized. The new compounds were characterized on the basis of spectral and elemental analyses. They were examined for their cytotoxic effects using SRB assay on four cancer cell lines HepG2, HCT116, CACO and MCF-7 in addition to the non-cancerous human cell line. They were non cytotoxic towards the normal derived cell line (IC50 value > 130 μM). Compounds 3, 6, 10 and 11 showed IC50 values less than 10 μM on three of the tested cell lines HepG2, HCT116 and CACO. Compounds 2h, 5, and 7b showed IC50 values less than or nearly equal 10 μM on HepG2, CACO and HCT116 respectively. Compounds 3 and 6 revelaed IC50 values less than 12 μM on MCF7. These obtained IC50 values are comparable with that of doxrubicin as it has showed IC50 range from 4.5 to 8.28 μM on the tested cell lines. All these promising derivatives showed inhibitory activity against EGFR with IC50 values less than 2 μM. The most potent EGFR inhibitors 7b (IC50 = 46 nM) and 10 (IC50 = 23 nM) showed to cause cell cycle arrest at G2/M phase and induce apoptosis. Molecular docking studies also were simulated to put insight and make better understanding to their structural features.