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Insulin-like growth factor binding protein 2 (IGF2BP2) fulfills a key role in the development of head and neck squamous cell carcinoma (HNSCC). Radiotherapy is an effective method to treat HNSCC; however, radiation resistance is the main reason for treatment failure. At present, the carcinogenic role of IGF2BP2 in terms of the proliferation of HNSCC and the radioresistance of its therapy remain poorly understood. In the present study, patients with HNSCC with higher IGF2BP2 expression levels were associated with shorter survival times. IGF2BP2 is significantly upregulated in HNSCC cells compared with irradiated cell. Based on functional studies, IGF2BP2 was found to promote HNSCC cell proliferation and tolerance to radiotherapy both in vitro and in vivo. In terms of the underlying mechanism, RIMS binding protein 2 (RIMBP2) was found to be highly expressed in HNSCC and to promote the proliferation of HNSCC and radiotherapy resistance. RIMBP2 was shown to be a direct target of IGF2BP2, activating endoplasmic reticulum stress in HNSCC. In addition, it has been demonstrated that IGF2BP2, as m6A reader, is able to promote RIMBP2 stability via binding to m6A sites in the RIMBP2-coding sequence region. Therefore, the present study has unveiled a potential mechanism via which IGF2BP2 promotes HNSCC development and radiotherapy resistance; moreover, from a therapeutic perspective, IGF2BP2 may serve as a potential therapeutic target and a valuable prognostic biomarker for patients with HNSCC who have developed tolerance towards radiotherapy.