The early detection of head and neck squamous cell carcinoma (HNSCC) has an important impact on the clinical prognosis. N6-methyladenosine (m6A) is involved in the post-transcriptional regulation of tumorigenesis and development. In this study, the prognosis and biological functions of m6A regulator targets in HNSCC were explored. RNA-Seq expression data and clinical information from TCGA-HNSCC and GSE23036 datasets were collected. The mRNA levels of IGF2BP2 and IGF2BP3 in tumor tissues were significantly up-regulated. Differential expression and functional enrichment analysis of potential targets for IGF2BP2 and IGF2BP3 obtained from the m6A2Target database showed that they were significantly enriched in cell cycle-related pathways. The Cox regression analysis was performed to establish a three-mRNA signature including PLAU, LPIN1 and AURKA. The prognostic effect was verified in the external dataset GSE41613. Further studies revealed that the three-mRNA signature was significantly associated with survival in the clinical subgroup. The ROC curve, Harrell consistency index and decision curve comparison used to compare the predictive effect of the three-mRNA signature and the other signatures in previous studies showed that the three-mRNA signature had better predictive effect on the prognosis of HNSCC patients. The three-mRNA signature expression were verified in HNSCC cell lines with qRT-PCR and Western blot. Sequence analysis showed that m6A-modification sites existed on PLAU, LPIN1 and AURKA genes. In conclusion, the three-mRNA signature has been proved to be useful on evaluating the prognosis and contributing to the personalized treatment of HNSCC, and IGB2BP2/3 were related to the cell cycle in HNSCC.