Oral squamous cell carcinoma (OSCC) is one of the most common head and neck malignancies. Advanced stages of the disease are associated with poor survival, highlighting a need for new treatment modalities. We previously showed that the proinflammatory cytokine interleukin‐18 (IL‐18) has a tumor suppressive role in OSCC. Here, we investigated the effects of IL‐18 on proliferation, migration, and invasion of OSCC cells ex vivo and in vitro, and in nude mouse xenografts. We report that expression of tankyrase 2 (TNKS2), β‐catenin, and N‐cadherin was higher in tumor cells than in normal mucosae, whereas the expression of IL‐18 and E‐cadherin was higher in normal than in tumor tissues. Elevated expression of IL‐18 (P < 0.01) and E‐cadherin (P = 0.034) was associated with tumor differentiation, whereas expression of TNKS2 (P < 0.01), β‐catenin (P = 0.012), and N‐cadherin (P < 0.01) was associated with tumor de‐differentiation. Furthermore, compared with the vector control, IL‐18 overexpression promoted tumor cell migration and invasion (P < 0.01), but inhibited growth of tumor cell xenografts (P < 0.05). At the protein level, expression levels of IL‐18 (P < 0.01), TNKS2 (P = 0.045), β‐catenin (P = 0.028), and N‐cadherin (P = 0.068) were upregulated in tumor cells after IL‐18 overexpression compared with those of the vector control mice, whereas expression levels of E‐cadherin (P = 0.045) were decreased. In conclusion, our data suggest that IL‐18 overexpression induces oral SCC cell invasion and metastasis by promoting the tumor cell epithelial–mesenchymal transition via the Wnt/β‐catenin signaling pathway.