Considering the critical importance of the RNA methylation process and the METTL3 gene in cancer and the absence of well-defined molecular targets responsible for modulating the cellular response to cisplatin in HNSCC, here, we conducted functional studies of cell cycle distribution, apoptosis, CD44/CD133 surface marker expression, and cell’s ability to colony formation after cisplatin treatment in vitro. This evidence concerns the gene CD44 and head and neck squamous cell carcinoma.