Upregulation of epidermal growth factor receptor (EGFR) signaling is observed in most head and neck squamous cell carcinomas (HNSCC) which makes it an attractive candidate for molecular targeted therapies. EGFR inhibitors have demonstrated clinical effectiveness in a subset of patients, however, many HNSCC tumors respond poorly to EGFR inhibitors leading to local recurrence and distant metastases. The purpose of this study is to determine if the glycolytic inhibitor 2-Deoxy-Glucose (2DG) enhances response of head and neck squamous cancer (HNSCC) cells to the EGFR inhibitor erlotinib (ERL). Using Cal-27 HNSCC cells, we showed that 2DG increased the anti-tumor activity of ERL, induced markers of autophagy and endoplasmic reticulum (ER) stress such as LC3B, CHOP, PERK and BIP, and increased the production of interleukin-1 beta (IL-1_). Mannose, an inhibitor of ER stress, reversed the anti-tumor effect of 2DG+ERL and suppressed 2DG+ERL-induced CHOP, BIP and IL-1_. The addition of exogenous IL-1_ failed to increase the anti-tumor effect of 2DG+ERL however, administration of an IL-1 receptor antagonist Anakinra, partially protected cells from the anti-tumor activity of 2DG+ERL in vitro and from ERL in vivo. These results suggest that 2DG may enhance the effect of ERL by increasing IL-1_ production via ER stress in HNSCC cells.