Oral cancer ranks the seventh in cancer-related deaths in men and also the thirteenth most common in women worldwide. The lymph node and distant metastasis are the major causes of death in oral cancer patients. Therefore, it is a critical need to identify new potential therapeutic agents against oral cancer metastasis. Oroxylin A (oro-A), a main bioactive flavonoid extracted from Scutellaria radix, has been reported to inhibit migration in various human cancers. Our previous study demonstrated that a long-term exposure to oro-A further suppress cell migration significantly than short-term oro-A exposure and without cytotoxicity on oral cancer cells treatment. Hence, we aimed to find out the anti-migration effects and underlying mechanisms of long-term oro-A exposure on oral cancer cells. In present study, we found that the migration abilities of the oral cancer cells long-term oro-A treatment may increased by chemokine ligand 2 (CCL2). It seems that CCL2 plays a critical role in anti-migration of long-term oro-A exposure. The CCL2 treatment was demonstrated to activate the protein levels of the p-ERK, p-JNK, NF-κB, MMP-2&9 signaling pathway. We also found that oro-A inhibit the metastasis via suppressing the expression of CCL2 in vivo. Our results indicate long term exposure to oro-A inhibits migration in human oral cancer cells through CCL2/ERK/NF-κB/MMP-2,9 signaling pathway.