Tongue squamous cell carcinoma (TSCC) is the most common oral squamous cell carcinoma. Despite significant advances in combined therapies, the 5-year survival rate of patients with TSCC has not notably improved; this is due to regional recurrences and lymph node metastasis. Grape seed proanthocyanidins (GSPs) are consumed as dietary supplements worldwide and possess anticancer activity against several different types of cancer. However, their effect on TSCC and the underlying mechanisms by which they function remain unclear. In the present study, it was identified that GSPs significantly inhibited the viability and induced the apoptosis of Tca8113 cells in a dose-dependent manner. This was associated with a significantly increased expression of the pro-apoptosis regulator BAX protein and a significantly decreased expression of the anti-apoptosis regulator Bcl-2 protein at 100??g/ml GSPs. In addition, at non-toxic concentrations GSPs significantly inhibited the secretion of matrix metalloproteinase-2?(MMP-2) and MMP-9 from Tca8113 cells, as well as their migration and invasion. Furthermore, it was demonstrated that GSPs significantly inhibited the phosphorylation of protein kinase?B (Akt) and IκB kinase, as well as the translocation of nuclear factor-κB?(NF-κB) into the nucleus of Tca8113 cells. Taken together, these results suggest that GSPs inhibit the proliferation, migration and invasion of Tca8113 cells through suppression of the Akt/NF-κB signaling pathway. This indicates that GSPs may be developed as a novel potential chemopreventive agent against TSCC.