The aim of the study is to investigate the effect of nardosinone (Nar) on neuronal injury induced by oxygen-glucose deprivation (OGD) in primary cortical cultures isolated from embryos at gestational day 14. MTT method was used to determine the dosage regimen of Nar in primary neuronal cultures and observe the influence of Nar on the neurons suffering OGD; Western blotting analysis was used to detect expressions of protein kinase A (PKA), Ras related protein 1 (Rap1), mitogen-activated protein kinase kinase 1 (MEK1) and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) of OGD-injured or uninjured primary cultured neurons after Nar treatment. Results showed that Nar (50 and 100 micromol x L(-1)) improved the cell viability during OGD damage (P < 0.01) and increased the expression of PKA, Rap1, MEK1 and p-ERK1/2 in injured neurons. Additionally, elevations of PKA, Rapl, MEK1 and p-ERK1/2 in uninjured neurons were caused by Nar (50, 100 and 200 micromol x L(-1)) with a dose-dependent tenclency as well (P < 0.01). In conclusion, Nar could protect against the neuronal injury exposed to OGD, which may be relevant to the promotion of PKA and ERK signaling pathway.