Increasing evidence and indications showed that cell fusion is crucial in tumor development and metastasis, and hypoxia, a closely linked factor to tumor microenvironment, which can lead to EMT, induces angiogenesis and metastasis in tumor growth. However, the relationship between hypoxia and fusion has not been reported yet. EMT will change some proteins in the epithelial cell surface and the changes of proteins in cell surface may increase cell fusion. This study found that hypoxia promotes the spontaneous cell fusion between Oral Squamous Carcinoma Cells (OSCCs) and Human Immortalized Oral Epithelial Cells (HIOECs). At the same time, Hypoxia can lead to EMT, and hypoxia-pretreated HIOECs increased fusion rate with OSCC, while the fusion rate was significantly reduced by DAPT, a kind of EMT blocker. Therefore, epithelial cells can increase spontaneously cell fusion with OSCC by EMT. Our study may provide a new insight to link among tumor microenvironment, cell fusion, and cancer.