Mesenchymal-epithelial transition factor (c-Met) is the only high affinity receptor for hepatocyte growth factor (HGF), and is frequently activated in many human cancers. However, little is known about the role of the HGF/c-Met signaling pathway in the progression of human oral squamous cell carcinoma (OSCC). This study evaluated the role of the HGF/c-Met signaling pathway in the progression of human OSCC. We found that the expression of c-Met was significantly increased in human OSCC tissues than in normal mucosa adjacent to the tumor (P<0.05), but was not correlated with clinicopathological parameters. Additionally, the selective c-Met inhibitor JNJ was found to inhibit cell viability and migration and promote apoptosis in OSCC cell lines, and also blocked the activation AKT, ERK1/2, and NF-κB p65; thus, suggesting that HGF/c-Met signaling may play an important role in the tumorigenic properties of OSCC cells via the AKT, ERK1/2, and NF-κB pathways. Collectively, these results indicated that HGF/c-Met signaling may serve essential roles in the progression of human OSCC, and may thus be a basis for the development of novel therapeutic approaches in the treatment of OSCC.