Icaritin, a hydrolytic product of icariin from the Epimedium genus, exerts anti‐tumor effects on a variety of tumor cell types, mainly by inhibiting cell proliferation and inducing apoptosis. However, little is known about the role of icaritin in cancer invasion and epithelial‐to‐mesenchymal transition (EMT). In the present study, the glioblastoma (GBM) cell line U87MG was used as a model to investigate the effects of icaritin on the invasion and EMT of cancer cells. Our results showed that icaritin significantly inhibited the invasion and EMT of GBM cells by targeting extracellular matrix metalloproteinase (EMMPRIN). Furthermore, our findings strongly indicated that the modulatory effect of icaritin on EMMPRIN was mediated via the PTEN/Akt/HIF‐1α signaling pathway. Our data provide the first experimental evidence of the inhibitory effect of icaritin on cancer cell invasion and EMT, thus highlighting the potential of icaritin to be employed as a promising anti‐cancer agent in the treatment of GBM. This article is protected by copyright. All rights reserved.