IFIT1 and IFIT3 are abundant products of interferon-stimulating genes. While the importance of IFIT1 and IFIT3 in the prognosis of cancer has been reported, the molecular basis of IFIT1 and IFIT3 in cancer progression remains unexplored. In the present study, we investigated the modes of action and the clinical significance of IFIT1 and IFIT3 in oral squamous cell carcinoma (OSCC). Ectopic expression of IFIT1 or IFIT3 induced OSCC cell invasion by promoting the epithelial-mesenchymal transition, whereas IFIT1 or IFIT3 knockdown exhibited opposite effects. Overexpression of IFIT1 or IFIT3 promoted tumor growth, regional and distant metastasis in xenograft and orthotopic nude mice models. Most importantly, IFIT1 or IFIT3 overexpression increased the levels of p-EGFRY1068 and p-AKTS473 in OSCC cells and also enhanced tumor inhibitory effect of gefitinib. By immunoprecipitation and LC-MS/MS analysis, we found that IFIT1 and IFIT3 interacted with ANXA2 that enhanced p-EGFRY1068 endosomal recycling. Depletion of ANXA2 using siRNA therefore abolished p-EGFRY1068 and p-AKTS473 expression in IFIT1- or IFIT3-overexpressed cells. Furthermore, a significant positive association of increased IFIT1 and IFIT3 expression with advanced T-stage, lymph node metastasis, perineural invasion, lymphovascular invasion, extranodal extension, and poor overall survival rate was confirmed in OSCC patients. We also found a statistically positive correlation of p-EGFRY1068 expression with IFIT1 and IFIT3 in OSCC tumors and poor clinical outcome in patients. Collectively, we demonstrated a novel role of IFIT1 and IFIT3 in driving OSCC progression and metastasis by interacting with ANXA2 and hence enhancing p-EGFR recycling and its downstream signaling.