In this study, our Arf1-targeting γ-dipeptides revealed anticancer activity in HNSCC cells, which may be linked to the blockade of the EGFR-Arf1 axis, suggesting that targeting the EGFR-Arf1 would constitute a feasible innovative strategy to fight against HNSCC and may provide an alternative strategy over currently used chemotherapy tolerance. This evidence concerns the gene EGFR and head and neck squamous cell carcinoma.