-Escin exhibits anticancer effects on a panel of established cancer cells. However, the effects of -escin on human osteosarcoma (OS) are still unknown. The aim of the present study was to investigate whether -escin was effective against OS both in vivo and in vitro. Our results showed that -escin induced dose- and time-dependent effects against MG-63, OS732, U-2OS, HOS and SAOS-2 cell proliferation. -Escin also exhibited excellent anti-proliferative and pro-apoptotic effects in an established OS xenograft model. -Escin and cytotoxic drugs, including cisplatin, methotrexate (MTX), doxorubicin (Dox) and ifosfamide (Ifos), synergistically inhibited proliferation of MG-63 and OS732 cells in vitro. Moreover, -escin induced apoptotic death, activated caspase-3, caspase-8 and caspase-9, and regulated expression of Bax and Bcl-2 in MG-63 cells. In addition, our results showed that -escin treatment reduced expression of p-PI3K, p-Akt and p-mTOR both in MG-63 cells and in an MG-63 xenograft OS model. Interestingly, SC79, which is an Akt activator, inhibited the anti-proliferative effects of -escin on MG-63 cells. Taken together, our data support the conclusion that -escin effectively inhibits OS proliferation both in vivo and in vitro. The inhibitory effect of -escin, at least in part, is due to the inactivation of the PI3K/Akt signalling pathway.