Objective To explore the effects of G1 on oxidative stress index in primary cortical neurons after oxygen glucose deprivation and the role of nuclear factor related factor 2 (Nrf2) during the process. Methods Primary cortical neurons from C57BL/6 embryonic mice were cultured for seven days and divided into six groups according to the random number table method (n=6): a control (C) group, an oxygen glucose deprivation/reoxygenation (OGD/R) group, a solvent group, a G1 group, a G1+control virus group and a G1+Nrf2 lentiviral group. The C group did not receive any treatment, while the OGD/R group was deprived of oxygen and glucose for 2 h before recovery. The solvent group was added with a proper amount of solvent 2 h after OGD followed by cultivation over 22 h. For the G1 group, OGD/R modeled neurons were used, and G1 was added into normal medium to reach a final concentration of 5 μmol/L to treat over 22 h. Primary neurons in the G1+control virus group were infected with control lentivirus to establish the model of OGD/R, before receiving the same treatment as the G1 group. Primary neurons in the G1+Nrf2 lentivirus group were infected with Nrf2 shRNA lentivirus to establish the model of OGD/R, before receiving the same treatment as the G1 group. The release of lactate dehydrogenase (LDH) was detected by spectrophotometry, and the cell survival was measured by cell counting kit‑8 (CCK‑8) assay. Then, the contents of reactive oxygen species (ROS), malonaldehyde (MDA), superoxide (SOD) and total antioxidant capacity (T‑AOC) were quantified by enzyme‑linked immunosorbent assay (ELISA). The levels of Nrf2 were examined by Western blot and immunofluorescence. Results Compared with the C group, both the OGD/R group and the solvent group presented remarkable increases in LDH, MOA and ROS contents, decreases in cell survival, SOD and T‑AOC contents, and increases in total Nrf2 and nuclear protein levels (P<0.05). Compared with the OGD/R group, the G1 group presented remarkable decreases in LDH, ROS and MDA contents, increases in cell survival, SOD and T‑AOC contents, and increases in total Nrf2 and nuclear protein levels (P<0.05). Compared with the G1 group and the G1+control virus group, the G1+Nrf2 lentivirus virus group produced decreases in cell survival, SOD and T‑AOC contents, and increases in LDH, ROS and MDA contents (P<0.05). There were no statistical differences in each indicator between the G1 group and the G1+contrl virus group (P>0.05). Conclusions G1 can alleviate OGD/R injury in primary neurons through increasing the activity of antioxidant enzymes via the Nrf2 pathway.