Osteoporosis is a systemic bone disease characterized by compromised bone strength, which predisposes the individual to an increased risk of fractures of the hip, spine, and other skeletal sites. Gynostemma pentaphyllum (of the family Cucurbitaceae) is known to reduce blood lipid, prevent arteriosclerosis, inhibit oxidation, reduce blood glucose, and regulate immunity. Gypenoside XVII is one of the bioactives in G. pentaphyllum, which inhibits receptor activator of nuclear factor-kappa B ligand-induced osteoclast production. Herein, we show that Gypenoside XVII improves the survival of MC3T3-E1 under high glucose environment. It also inhibits the apoptosis of MC3T3-E1 cells in high glucose environment. In addition, Gypenoside XVII promotes osteogenic differentiation of MC3T3-E1 cells in high glucose environment. Mechanically, we found that Gypenoside XVII inhibited high glucose-induced apoptosis and facilitated osteogenic differentiation via activating the PI3K/AKT pathway. These data suggest that Gypenoside XVII might be a potential therapeutic drug in the treatment of osteoporosis.