Bacterial infection contributes to tumor development and malignant progression. Fusobacterium nucleatum (F. nucleatum) is reported to promote oral squamous cell carcinoma. However, molecular bases of F. nucleatum regulating oral cancer cells have not been fully elucidated. We report here that F. nucleatum down-regulates p53 and E-cadherin via the Wnt/NFAT pathway to promote cisplatin-resistance and migration in oral squamous carcinoma cells. We pretreated Cal-27 and HSC-3 cells with F. nucleatum and the survival rates against cysplatin (Cis-diamminedichloroplatinum, CDDP) were significantly higher in treated cells. The expressions of migration and apoptosis-related proteins like E-cadherin and p53 were lower in western blot analysis. We observed that F. nucleatum was an activator of the Wnt/NFAT pathway. The expression levels of the Wnt pathway gene wnt5a and Nuclear factors of activated T cells 3 (NFATc3) were notably higher in treated cells. With the inhibition effect of NFAT-inhibitory peptide VIVIT, the expressions of E-cadherin and p53 in response to F. nucleatum infection were up-regulated reversely. We concluded that F. nucleatum might promote cisplatin-resistance and migration of oral squamous cell carcinoma cells through the Wnt/NFAT pathway.