In conclusion, we identified novel lncRNA signatures including HOXC-AS2, FOXD2-AS1, LINC00460, AC022031.2, AP002957.1, AP002478.1, and AC011369.1 that could predict HNSCC prognosis independently, and we furtherly validated the cancer-promoting function of FOXD2-AS1 in HNSCC in vitro, which was similar to that in other kinds of cancers. This evidence concerns the gene FOXD2 and head and neck squamous cell carcinoma.