Together, the results from this study have identified for the first time that bioactive proanthocyanidins from grape seeds inhibit the invasiveness of human HNSCC cells and that this effect involves: (i) the inhibitory effect of GSPs on EGFR expression, (ii) the inhibitory effect of GSPs on the activation of the ERK1/2 proteins and inactivation of NF-κB, and (iii) reversal of the EMT. Here, MAPK3 is linked to head and neck squamous cell carcinoma.