Isorhapontigenin (ISO), a naturally phytopolyphenol compound existing in Chinese herb, apples, and various vegetables, has attracted extensive interest in recent years for its diverse pharmacological characteristics. Increasing evidences reveal that ISO can inhibit cancer cell growth by induced apoptosis, however, the molecular mechanisms is not fully understood. In this study, we found for the first time that ISO apparently induced cell growth inhibition and apoptosis by targeting EGFR and its downstream signal pathways in prostate cancer (PCa) cells both in vitro and in vivo, whereas no obviously effect on normal prostate cells. From the results, we found that ISO competitively targeted EGFR with EGF and inhibited EGFR auto‐phosphorylation, and then decreased the levels of p‐Erk1/2, p‐PI3 K, and p‐AKT, and further induced down‐regulation of p‐FOXO1 and promoted FOXO1 nuclear translocation; and finally resulted in a significantly up‐regulation of Bim/p21/27/Bax/cleaved Caspase‐3/cleaved PARP‐1 and a markedly down‐regulation of Sp1/Bcl‐2/XIAP/Cyclin D1. Moreover, our experimental data demonstrated that treatment of ISO decreased protein level of AR via both inhibiting the expression of AR gene and promoting the ubiquitination/degradation of AR proteins in proteasome. In vivo, we also found that ISO inhibited the growth of subcutaneous xenotransplanted tumor in nude mice by inducing PCa cell growth inhibition and apoptosis. Taken together, all findings here clearly implicated that EGFR‐related signal pathways, including EGFR‐PI3K‐Akt and EGFR‐Erk1/2 pathways, were involved in ISO‐induced cell growth inhibition and apoptosis in PCa cells, providing a more solid theoretical basis for the application of ISO to treat patients with prostate cancer in clinic. In this study, we find for the first time that ISO competitively targets EGFR with EGF and inhibits the auto‐phosphorylation of EGFR at Tyr1173, resulting in inactivation of EGFR and its downstream signal pathways, including EGFR/PI3K/Akt pathway, and EGFR/Erk pathway; and finally induce cell growth inhibition and apoptosis by further activating FOXO1 and inactivating androgen receptor (AR) in prostate cancer cells.