Objective To explore the mechanism of ginsenoside Rg3 on the fibrosis and biological activity of HMC cells induced by high glucose based on Nrf2/ARE signaling pathway. Methods Human mesangial cells were divided into 5 groups: NC group, HG group, Rg3A group, Rg3Bgroup and Rg3C group. Cell proliferation, invasion, apoptosis and cell cycle were detected. Fluorescence probe DCFH-DA method was used to detect ROS content in cells. The expressions of Nrf2, HO-1, TGF-β, IV-C and FN were detected by Western blot.Results Compared with NC group, the proliferation activity and invasion ability of HG group were significantly increased (P＜0.05). Compared with HG group, the proliferation activity and invasion ability of Rg3A, Rg3B and Rg3C groups were significantly decreased (P＜0.05). The proliferation activity and invasion ability of Rg3C group were significantly lower than those of Rg3A group and Rg3B group (P＜0.05). Compared with NC group, the apoptosis rate of HG group was significantly decreased, and G1 phase was increased (P＜0.05). Compared with HG group, the apoptosis rate of Rg3A group, Rg3B group and Rg3C group was significantly increased, and the G1 phase was significantly decreased with an increasing trend (P＜0.05), and the apoptosis rate and cell cycle change of Rg3C group were the most significant (P＜0.05). Compared with NC group, ROS content in GH group was significantly increased (P＜0.05). Compared with GH group, ROS content in Rg3A, Rg3B and Rg3C groups was significantly decreased (P＜0.05). Compared with NC group, the protein expressions of NNrf2 and HO-1 in GH group were significantly decreased (P＜0.05). Compared with GH group, the protein expressions of Nrf2 and HO-1 in Rg3A group, Rg3B group and Rg3C group were significantly increased, and the protein expression in Rg3C group was most significantly increased (P＜0.05). Compared with NC group, TGF-β, ⅳ-c and FN in GH group were significantly increased (P＜0.05). Compared with GH group, the expressions of TGF-β, IV-c and FN in Rg3A, Rg3B and Rg3C groups were significantly decreased, and the expressions of TGF-β, IV-C and FN in Rg3C group were lower than those in Rg3B group and Rg3A group (P＜0.05). Conclusion Ginsenoside Rg3 can inhibit the proliferation and invasion of HMC cells induced by high glucose, promote HMC cell apoptosis, and enhance the antioxidant capacity of mesangial cells by regulating the protein related to the Nrf2/ARE signaling pathway in the cell.