Being the most malignant primary brain tumor in humans, glioblastoma multiforme (GBM) has a fairly poor patient survival after current combined treatment with chemotherapy, radiation, and surgery. Ginsenoside Rh2 (GRh2) has been reported to have a therapeutic effect on some tumors, and we recently reported its inhibitory effect on GBM growth in vitro and in vivo, possibly through an epidermal growth factor receptor (EGFR) signaling pathway. Here, using specific inhibitors, we found that the activation of EGFR signaling promoted GBM growth through PI3k/Akt/mTor signaling pathways. Moreover, GRh2 efficiently inhibited activation of this pathway at the receptor level. Together with our previous findings, these data suggest that GRh2 may suppress GBM growth through its competition with EGFR ligands for binding to the EGFR, and binding to EGFR by GRh2 does not lead to receptor phosphorylation. Thus, our data highlight a previous unappreciated role for GRh2 to inhibit EGFR signaling. GRh2 thus appears to be a promising therapy for cancers that require EGFR signaling to growth.