Nasopharyngeal carcinoma (NPC) is a cancerous tumor that develops in the nasopharynx epithelium and typically has squamous differentiation. The squamous phenotype is evident in immunohistochemistry, with diffuse nuclear positivity for p63 and p40. Nonetheless, a few NPCs have been identified by clinicopathological diagnosis that do not exhibit the squamous phenotype; these NPCs are currently referred to as non-squamous immunophenotype nasopharyngeal carcinomas (NSNPCs). In a previous work, we have revealed similarities between the histological appearance, etiology, and gene alterations of NSNPC and conventional NPC. According to ultrastructural findings, NSNPC still falls under the category of non-keratinized squamous cell carcinoma that is undifferentiated. NSNPC has an excellent prognosis and a low level of malignancy, according to a retrospective investigation. Based on prior research, we investigated the molecular mechanism of NSNPC not expressing the squamous phenotype and its biological behavior. IHC was used to determine the expression of EGFR, PI3K, AKT, p-AKT, mTOR, p-mTOR, Notch, STAT3 and p-STAT3 in a total of 20 NSNPC tissue samples and 20 classic NPC tissue samples. We obtained human NPC cell lines (CNE-2,5-8F) and used EGFR overexpression plasmid and shRNAs to transfect them. To find out whether mRNA and proteins were expressed in the cells, we used Western blotting and qRT-PCR. Cell biological behavior was discovered using the CCK-8 assay, cell migration assay, and cell invasion assay. EGFR, PI3K, p-AKT and p-mTOR proteins were lowly expressed in NSNPC tissues by immunohistochemistry, compared with classical NPC. In the classical NPC cell lines CNE-2 and 5-8F, overexpression EGFR can up-regulate the expression of p63 through the PI3K/AKT/mTOR pathway, and promote the proliferation, migration, and invasion of nasopharyngeal carcinoma cells. At the same time, knockout of EGFR can down-regulate p63 expression through the PI3K/AKT/mTOR pathway, and inhibit the proliferation, migration, and invasion of nasopharyngeal carcinoma cells. The lack of p63 expression in NSNPC was linked with the inhibition of the EGFR/PI3K/AKT/mTOR pathway, and NSNPC may be a variant of classical NPC.