It is very promising to target the extracellular domain of epidermal growth factor receptor (EGFR) for developing novel and selective anticancer therapies. Herein, we report the discovery of a novel small molecule, <b>M-2-5</b>, from a one-bead-two-compound (OBTC) cyclic γ-AApeptide library. The molecule was found to bind tightly to the extracellular domain of EGFR. Intriguingly, this molecule could also effectively antagonize EGF-stimulated EGFR phosphorylation and downstream signal transduction. Furthermore, together with its remarkable resistance to proteolytic degradation, <b>M-2-5</b> was shown to effectively inhibit cell proliferation and migration in vitro and suppresses the growth of tumor in the A549 xenograft model in vivo, highlighting its potential therapeutic application for cancer treatment.