Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC-3 and Ca9-22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal-regulated kinases 1/2 (ERK1/2), but not c-Jun N-terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx-suppressed transwell migration and MMP-2/-9 activities in HSC-3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells.