Malignant glioma is featured with high invasiveness. However, current drugs have limited outcomes to impair glioma invasion. The activation of Akt pathway is one of major mechanisms of glioma invasion. In this study, we investigated if aplysin, a natural compound from seaweed, has an inhibitory effect on the invasiveness of glioma cells. Aplysin was found to reduce the number of invasive U-87 MG ... [Show full abstract] and U-251 MG glioma cells, as well as primary glioma cells, in a dose-dependent manner. Invasion-associated proteins were found to be underexpressed in aplysin-treated glioma cells. Akt pathway was inactivated by aplysin and reactivating Akt pathway rescued the inhibitory effect of aplysin on invasion-associated proteins and the invasiveness of U-87 cells. Aplysin has no cytotoxicity to normal cells. Collectively, aplysin can suppress the invasion of glioma cells through suppressing Akt pathway.