The low median survival rate of oral squamous cell carcinoma (OSCC) is associated with chemotherapeutic resistance. Niclosamide is an oral anti-helminthic drug, its anti-cancer effect has been reported in recent years. However, the effect of niclosamide on OSCC remains largely unknown. In this study, we, for the first time, investigated the underlying mechanisms from cell cycle arrest and let-7a/STAT3 axis through CCK-8, cell cycle, apoptosis, wound healing, Transwell invasion, generation of stable cell line, real-time PCR, and western blot assays using two OSCC cell lines WSU-HN6 and Tca83. We showed that niclosamide could inhibit OSCC cells proliferation through causing cell cycle arrest in G1 phase and promoting apoptosis, while the cell cycle-related proteins MCM2, MCM7, CDK2 and CDK4 were downregulated and the apoptosis-related proteins p53 and cleaved caspase-3 were upregulated. Furthermore, niclosamide could inhibit migration and invasion of OSCC through upregulation of let-7a expression and downregulation of p-STAT3 expression. What is more, we established the stably expressing let-7a cell line (HN6-let-7a). Like niclosamide, HN6-let-7a could decrease the ability of the cell migration, invasion as well as the expression of p-STAT3. Collectively, our study finds the new mechanisms that niclosamide inhibits OSCC proliferation through causing cell cycle arrest in G1 phase via downregulation of the above cell cycle-related genes; promotes OSCC apoptosis through upregulation of pro-apoptotic genes; decreases migration and invasion of OSCC by let-7a/STAT3 axis, thus providing a preferred therapeutic candidate for OSCC in future.