Identifying the key molecules that enhance chemo‑ and radiosensitivity in head and neck squamous cell carcinoma (HNSCC) as well as reliable biomarkers for predicting recurrence and metastasis would be desirable to improve the prognosis of HNSCC. Previously, we have reported that Regenerating gene III (REG III) expression was associated with an improved survival rate for patients with HNSCC. In addition, resveratrol (3,4',5‑trihydroxystilbene) significantly increased REG III expression in HNSCC cells, and significantly inhibited cell growth, enhanced chemo‑ and radiosensitivity, and blocked the cancer invasion of HNSCC cells in vitro. In the present study, the effect of resveratrol on cancer progression in HNSCC was investigated in vivo using a xenograft nude mouse model. The results revealed that resveratrol increased the mRNA level of REG III in vivo, which was in agreement with our previous in vitro findings. Furthermore, REG III increased the antitumor effect of radiation or cisplatin in vivo, and resveratrol sensitized HNSCC to irradiation and cisplatin in vivo. These results indicated that resveratrol could increase the efficacy of cisplatin and irradiation through the REG III expression pathway, resulting in the inhibition of HNSCC progression in vivo.