Nasopharyngeal carcinoma (NPC) is notorious for its aggressiveness and high metastatic potential. NPC patients with distant metastasis have a particularly poor prognosis; however, evaluating metastatic potential by expression profiles of primary tumors is challenging. This study aimed to investigate the association between activation of epidermal growth factor receptor (EGFR) signaling and NPC metastasis and the underlying mechanisms. We found an association between EGFR protein overexpression and intense EGFR immunostaining in NPC samples with advanced tumor node metastasis stage, clinical stage, and distant metastasis in NPC patients. Exogenous EGF stimulates NPC mobility and invasiveness in vitro. Activation of EGFR signaling prompted PKM2 translocation to the nucleus. Silencing either EGFR or PKM2 attenuates NPC cell aggressiveness in vitro and in vivo. Blocking EGFR signaling with cetuximab suppressed NPC cell invasiveness in vitro and metastatic potential in vivo. Comprehensive analyses of transcriptome profiles indicated that the EGFR-PKM2 axis activates a number of novel metastasis promoters, including F3, FOSL1, EPHA2, ANTXR2, and AKR1C2. Finally, we found that the metastasis-promoting function of the EGFR-PKM2 axis is dependent on nuclear PKM2 regulation of the transcription of metastasis-related genes, including FOSL1 and ANTXR2. Our study indicates that EGFR-PKM2 signaling promotes NPC cell invasion and metastasis through induction of FOSL1 and ANTXR2 and identifies EGFR as a promising biomarker for predicting the risk of distant metastasis.