Oridonin (ORI) is a natural diterpenoid presented in some medicinal plants. The effects of pre-treatments from ORI against MPP+- or kainic acid (KA)-induced damage in nerve growth factor (NGF)-differentiated PC12 cells were investigated. Results showed that pre-treatments of ORI at 0.25–2 μM enhanced the viability and plasma membrane integrity of NGF-differentiated PC12 cells. MPP+ or KA exposure down-regulated Bcl-2 mRNA expression, up-regulated Bax mRNA expression, increased caspase-3 activity and decreased Na+-K+ ATPase activity. ORI pre-treatments at test concentrations reversed these changes. ORI pre-treatments decreased reactive oxygen species production, raised glutathione level, and increased glutathione peroxidase, glutathione reductase and catalase activities in MPP+ or KA treated cells. ORI pre-treatments lowered tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and prostaglandin E2 levels in MPP+ or KA treated cells. ORI also diminished MPP+ or KA induced increase in nuclear factor-κB binding activity. MPP+ exposure suppressed tyrosine hydroxylase (TH) mRNA expression and decreased dopamine content. KA exposure reduced glutamine synthetase (GS) mRNA expression, raised glutamate level and lowered glutamine level. ORI pre-treatments at 0.5–2 μM up-regulated mRNA expression of TH and GS, restored DA and glutamine content. These findings suggested that oridonin was a potent neuro-protective agent against Parkinson's disease and seizure. Display omitted •Oridonin (ORI) against MPP+ or kainic acid (KA) induced damage in NGF-differentiated PC12 cells were examined.•ORI pre-treatments decreased caspase-3 activity and increased Na+-K+ ATPase activity.•ORI diminished MPP+ or KA induced increase in nuclear factor-κB binding activity.•ORI increased mRNA expression of tyrosine hydroxylase and glutamine synthetase.•Oridonin was a potent neuro-protective agent against Parkinson's disease and seizure.