Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes. The liver is an important organ responsible for the development of insulin resistance, and exploring liver glucose metabolism is important to study insulin resistance. We first established the model of insulin resistance in HepG2 cells and then treated them with different concentrations of ginsenoside-Rg1. The results showed that ginsenoside-Rg1 is not toxic to HepG2 cells. In addition, ginsenoside-Rg1 relieved the insulin-induced insulin resistance in HepG2 cells. Furthermore, ginsenoside-Rg1 increased the uptake of glucose by reducing reactive oxygen species and down-regulating the phosphorylation level of p38 MAPK. In addition, ginsenoside-Rg1 also decreased the output of glucose by increasing Akt phosphorylation and reducing GSK3β expression. In conclusion, ginsenoside-Rg1 can alleviate the insulin resistance through increasing the uptake of glucose and decreasing the output of glucose.