The epithelial-mesenchymal transition (EMT) is a pivotal event in cancer cell invasion and metastasis. Emerging evidence suggests that rhapontigenin (Rha) may impede the progression of cancer by disrupting angiogenesis and the EMT. However, the underlying mechanism of Rha has not yet been clarified. In this study, we used transforming growth factor β (TGF-β) to trigger EMT in diverse types of cancer cells and revealed that Rha inhibited TGF-β-induced EMT and derived‑cell invasiveness. The effects of TGF-β were blocked by Rha via interference with the PI3K/AKT/mTOR/GSK3β/β‑catenin signaling pathway. Furthermore, Rha also inhibited TGF-β‑induced expression of transcription regulators Snail and hypoxia-inducible factor 1α (HIF-1α) by causing their degradation by the 26S proteasome. Surprisingly, although HIF-1α was degraded with Snail as a result of Rha exposure, HIF-1α was not a key factor involved in TGF-β-mediated EMT induced by Rha. Knocking-down Snail expression, but not HIF-1α expression, by RNA interference dramatically reversed TGF-β-mediated EMT. Moreover, Rha abolished TGF-β-triggered cell invasiveness. Our results demonstrate that Rha inhibits TGF-β-induced EMT in cancer cells by suppressing the activity of the PI3K/AKT/mTOR pathway. Therefore, Rha may represent a new route for therapeutic intervention in cancer patients and merits future studies to assess its potential.