As a traditional Chinese medicine and functional food, Polygonatum sibiricum contains many bioactive compounds with multiple biological activities. Presently, we obtained three extracts from Polygonatum sibiricum by different solvents and comparably analyzed their total phenols, flavonoids, and chemical compositions. Meanwhile, the antioxidant activity and the attenuation of palmitic acid (PA)-induced hepatic oxidative stress of these extracts were further investigated. The results showed that the active substances in Polygonatum sibiricum were inclined to dissolve in ethanol (EE), and twenty compounds were identified. EE exhibited the best antioxidant activity to scavenging DPPH and ABTS free radicals, as well as reducing power. Meanwhile, extracts from Polygonatum sibiricum, especially EE, could significantly increase the activity of SOD and HO-1 and ameliorate PA-induced oxidative stress in HepG2 cells through Nrf2-related pathways. Furthermore, EE could significantly inhibit the activity of α-glucosidase and effectively reduce the rapid rise of blood glucose induced by sucrose loading.