This study found that metformin significantly enhanced the anticancer effect of dasatinib in HNSCC cells by inducing AMPK‐dependent ER stress. In vitro, metformin combined with dasatinib led to greater apoptosis (p < 0.05) and EGFR degradation than dasatinib alone. In vivo, metformin‐dasatinib combination therapy significantly reduced tumor growth in xenograft models (p < 0.05), suggesting a synergistic effect that could improve treatment outcomes in HNSCC. The gene discussed is EGFR; the disease is neoplasm.