Novel series of pyrrolizine Schiff bases has been synthesized then biologically evaluated as potential anticancer agents. The starting compounds,7-cyano-6-amino-N-(4-(un)substituted-phenyl)-2,3-dihydro-1H-pyrrolizine-5- carboxamides 17a–c, were reacted with different aldehydes to give the target compounds 18-20. Structural characterizations of the novel compounds were performed using spectral and elemental analysis. The anticancer activity of these compounds was evaluated using Sulforhodamine-B (SRB) assay method .All of these compounds showed anticancer activity against bothHEPG2 and MCF7 cancer cell lines comparable to that of the standard Doxorubicin (HEPG2 IC50 =0.00699μM/ml). Most of compounds are more active against (MCF7) than (HEPG2) cell lines. Compound 18c showed the highest anticancer activity with IC50 value 0.250μM/ml against (MCF7).While, Compound18b was the most potent one against liver (HEPG2) with IC50 value 0.784 μM/ml. Modeling studies into ATP binding site of EGFR tyrosine kinase were done to predict their scores and mode of interaction with amino acid residues. Furthermore selectivity of the prototypes(18-20a) on normal Wish cell was evaluated and showed IC50 of 0.946, 1.322 and 1.122 respectively