Combined radiotherapy and EGFR-targeted therapy regimen is preferred for patients with advanced oral cancer because it improves local cancer control and overall survival (OS) than radiotherapy alone. However, 50% of patients still develop local recurrence because of radioresistance. And some tumors showed radioresistance after inhibiting EGFR and the downstream signalling ERK, AKT,etc. Therefore, this study sought to identify new targets involved in resistance to EGFR-targeted therapy combined with radiotherapy.Endoplasmic reticulum stress (ERS) plays an important role in the regulation of radio- and chemoresistance in many malignancies. In this study, we investigated the role of EGFR and ERS signaling in the radioresistance of oral cancer. EGFR and ERS signalling pathway activation in KBoral carcinoma cells and the constructed corresponding radioresistant KBR cells after irradiation were detected by western blotting and real-time quantitative PCR. The radioresistance ofEGF-EGFR was detected using the colony formation assay. The cell apoptosis was detected by flow cytometry. And Cell proliferation was analysed using a Cell Counting Kit-8 (CCK-8) manufacturer’s protocol. DNA double-strand breaks and autophagy was detected by immunofluorescence. Immunohistochemistry was performed on 51 oral squamous cell carcinoma tissue specimens. The correlation between GRP78 and the prognosis of oral cancer patients was analysed using the Kaplan-Meier method. Herein, we constructed radioresistant oral cancer cells (KBR) and confirmed that EGF induced radioresistance, which could be reversed by silencing EGFR. Moreover, EGF activated radiation-induced ERS signalling PERK/ATF6/IRE1-GRP78 in oral cancer cells, whereas silencing EGFR inhibited the aforementioned functions. And EGF significantly increased the radiation-induced phosphorylation of ERK and AKT, while silencing PERK, IRE1α and ATF6 did not alter this effect. Consistent with others, ERS signalling in parallel with AKT/ERK in downstream of EGFR, and therefore may be targeted in amelioration of EGF-EGFR. In addition, silencing EGFR and the EGFR-targeted inhibitors cetuximab or nimotuzumab could inhibit radiation-induced DNA double-strand break (DSB) repair and autophagy, but increase radiation-induced cell apoptosis. The use of the ERS activators tunicamycin and thapsigargin could counteract this effect. Immunohistochemistry results showed that the ERS chaperone GRP78 was associated with poor prognosis of oral cancer (p < 0.05). These data indicate that inhibition of EGFR could reverse the radioresistance of oral cancer cells by inhibiting radiation-induced activation of ERSsignalling PERK/ATF6/IRE1-GRP78.