Dihydroartemisinin(DHA) is the active metabolic derivative of artemisinin. DHA has potential therapeutic effects on glioma but the detailed mechanism is unclear. In this study, we investigated the role and the underlying mechanisms of DHA in its inhibition of glioma cells. U87 cells are wild-type p53 glioblastoma cells and U251 cells contain mutant p53. DHA inhibited the proliferation, migration and invasion of glioma cells in a dose-dependent manner. DHA promoted reactive oxygen species production and activated p53 in two glioma cell lines, U87 and U251. In U87 cells, DHA significantly up-regulated the expression of p–β-catenin (S45) and inhibited EGFR, β-catenin, p–β-catenin (Y333) and matrix metalloprotease7/9 activity. In U251 cells, DHA significantly up-regulated p–β-catenin (S45), p–β-catenin (Y333) and EGFR, but the expression of β-cateninwas unchanged. We also found that DHA and sh–β-catenin prevented the proliferation of U87 and U251 cells in vivo. In conclusion, DHA inhibited the migration and invasion of human glioma cells with different types of p53 via different pathways.