Objective: Oral cancer is known to synthesize arachidonic acid metabolites. Cycloxygenases (COXs) and lipooxygenase (LOXs) were involved in arachidonic acid metabolism. The aim of this study was to evaluate the effect of arachidonic acid metabolism inhibition on the invasion and matrix metalloproteinase (MMP) activity of oral cancer cells. Methods: Low (HN4) and high (HN12) metastatic oral cancer cell lines were treated with selective COX-1 inhibitor (Aspirin), COX-2 inhibitor (NS-398), non-selective COX inhibitor (Sulindac), LOX inhibitor (NDGA) and both COX and LOX inhibitors (ETYA). Cell invasion was performed using Matrigel-based chemoinvasion assay. MMP-2 and MMP-9 activities of the treated tumor cells were determined using gelatin-based zymography assay. All treatment was performed on triplicate. Assessment of statistical differences was determined by two-way ANOVA. Results: All inhibitors caused a significant reduction in invasiveness of the tumor cells compared to controls. However, none of the drugs tested showed significant difference in cell invasion. Inhibitory effects of Aspirin (1.5mM), NS-398 (0.1mM), Sulindac (0.2mM), NDGA (0.1mM) and ETYA (0.1mM) on the invasiveness of HN4 were 52.39%, 57.03%, 45.01%, 46.59% and 42.08%, respectively (p>0.05). No significant inhibition of invasion was also seen in HN12 treated with Aspirin (11.83%), NS-398 (20.92%), Sulindac (22.82%), NDGA (38.84%) and ETYA (57.45%). NDGA and ETYA caused significant reduction in MMP-2 and MMP-9 activities of HN4 and HN12 compared to that of Aspirin, NS-398 and Sulindac. Conclusion: Our results suggest that arachidonic acid metabolism may play an important role in the invasion and proteolytic activity of oral cancer cells.