Purpose One strategy for treating cancer is to prevent metastatic spread. Matrix metalloproteinase are considered potential targets for cancer therapy because of their role in degrading the extracellular matrix and fostering tumor progression. In some cancer models, the small molecule 1,2,3,4,6-Penta-O-galloyl-β-d-glucose (PGG) exhibited inhibitory properties against matrix metalloproteinase (MMP) related metastatic activity. This study explored whether PPG may limit the potential for metastatic spread in oral squamous cell carcinoma. Materials and methods This study used Cal-27 cells, a cell line derived from a squamous cell carcinoma line of human tongue origin, and antibodies for MMP-1,-2,-3,-9,-13, MT1-MMP signal transducers and activators of transcription 3 (Stat3), and pStat3. Cells were treated with PGG at different concentrations to evaluate MMP and Stat3 activation. Expansion assays were performed using Matrigel matrixes to measure Cal-27 invasiveness in the presence of PGG. Results PGG decreased the expression of MMP-2,-9 and-13 in the Cal-27 cell line, decreased phosphorylation of Stat3 and reduced gene expression of MMP-2,-9 and-13. As observed in Matrigel expansion assays, PGG limited the invasiveness of Cal-27 cells in a dose-dependent manner. Conclusion PPG is a small molecule inhibitor with the potential to reduce the expression of the matrix metalloproteinases and to limit the invasiveness of the squamous cell carcinoma line, Cal-27. By controlling the expression of molecules responsible for metastasis, PPG may offer a new therapeutic option for treating oral squamous cell carcinoma.