Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) has a role in the occurrence and progression of multiple types of tumors. However, its role in cervical cancer (CC) remain unknown. EBP50 was reported to interact with epidermal growth factor receptor (EGFR) and regulate EGFR signaling in CC HeLa cells. In this study, the effect of EBP50 expression on CC cell proliferation and prognosis of CC patients by regulating EGFR signaling was investigated. We found that EBP50 expression level was significantly downregulated in CC tissues. EBP50 expression negatively correlated with CC cell proliferation, cell cycle and the activation of EGFR-mediated ERK signaling. EBP50 knockdown abolished its inhibition on EGF-induced ERK activation, suggesting EBP50 regulated EGFR signaling. In order to further explore EBP50 regulated EGFR signaling via interaction, we constructed EBP50_DD mutant which disrupted its interaction with EGFR. EBP50_DD overexpression attenuated the inhibition of EBP50_WT on EGFR-mediated ERK signaling, further revealing EBP50 regulated EGFR signaling via its interaction with EGFR. EGFR activation was associated with poor prognosis of CC patients. EBP50 could not predict the prognosis of all CC patients. However, after ruling out patients with egfr/ErbB mutation or copy number variation (CNV) and (chemo)radiation, which caused continuous EGFR activation and affected the prognosis of patients, respectively, EBP50 expression level exhibited the prognosis prediction ability, revealing EBP50 affected prognosis of CC patients via regulating EGFR signaling. In conclusion, EBP50 played an important role in CC cell proliferation and prognosis prediction of CC patients by interacting with EGFR and regulating EGFR signaling. EBP50 might be a potential precise therapeutic target or prognostic marker for CC patients.