Objective: Metastasis process is a complex process involving penetration through basement membrane barriers. The purpose of this study was to investigate whether COX and LOX inhibitors affected the invasion of oral cancer cells. Materials and Methods: To assess the effect of NS-398 (the selective COX-2 inhibitor) and NDGA (the selective LOX inhibitor) on the invasion of low invasive (HN4) and high invasive (HN12) oral cancer cells, we performed Matrigel invasion assays. MMP-2 and MMP-9 activities in conditioned media of each cancer cell line that exposed with NS-398 or NDGA for 48 h were determined by gelatin zymography. Results: NS-398 and NDGA significantly decreased the invasion of HN4 and HN12 when compared with that of control cells (p<0.05). The inhibitory effect was obviously demonstrated in HN4 cells in comparison to HN12 cells (P<0.05). NS-398 and NDGA showed a significant reduction in the levels of proMMP-2 and pro MMP-9 in both cell lines (p<0.05). However, a reduction in MMP-9 activity was markedly observed when oral cancer cells were treated with NDGA. NS-398 and NDGA had less effect on the activities of MMP-2 and MMP-9 of HN4 cells in comparison to HN12 cells (p<0.05). Conclusion: Our findings suggest that inhibitors of arachidonic acid metabolism influence the invasion of low and high invasive oral cancer cells.