Recent studies have confirmed that the combined use of anti-cancer drugs with ionizing radiation (IR) could improve the sensitivity of osteosarcoma (OS) cells. Therefore, it is necessary to identify potential effective drugs for the enhancement of IR-radiosensitivity. In the current study, we found that 20, 10, 5, and 1 μM of ginseng polysaccharide (GPS) significantly suppressed MG-63 cell viability with or without γ-ray radiation in a dose- and time-dependent manner. Strikingly, 20 μM of GPS combined with 5 Gy treatment suppressed colony formation capacity by nearly 13.75∼fold compared with IR treatment alone. Our results showed that GPS could markedly induce early apoptosis and autophagy in MG-63 cells. A higher drug concentration and a greater exposure dose were directly associated with more apoptosis and autophagy in cells. Western blot analysis showed that GPS decreased the phosphorylation of p38 and AKT as well as the protein expression of Bax and cleaved-caspase3. In summary, GPS inhibited proliferation and increased apoptosis and autophagic death in OS cells, indicating that GPS may be a potential effective auxiliary drug for improving the IR sensitivity of OS patients.