Summary Background In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI3K/AKT/caspase 3 pathway are strongly implicated in dopaminergic neuronal death in Parkinson's disease (PD). This study aims to investigate how simvastatin affects 6‐hydroxydopamine‐lesioned PC12 via regulating PI3K/AKT/caspase 3 and modulating inflammatory mediators. Methods 6‐hydroxydopamine‐treated PC12 cells were used to investigate the neuroprotection of simvastatin, its association with the PI3K/AKT/caspase 3 pathway, and antiinflammatory responses. Dopamine transporters (DAT) and tyrosine hydroxylase (TH) were examined in 6‐hydroxydopamine‐treated PC12 after simvastatin treatment. Results Simvastatin‐mediated neuroprotection was associated with a robust reduction in the upregulation induced by 6‐OHDA of inflammatory mediators including IL‐6, COX2, and TNF‐α. The downregulated DAT and TH levels in 6‐OHDA‐lesioned PC12 were restored after simvastatin treatment. Simvastatin reversed 6‐OHDA‐induced downregulation of PI3K/Akt phosphorylation and attenuated 6‐OHDA‐induced upregulation of caspase 3 in PC12. Furthermore, the PI3K inhibitor LY294002 pronouncedly abolished the simvastatin‐mediated attenuation in caspase 3. Conclusions Our results demonstrate that simvastatin provides robust neuroprotection against dopaminergic neurodegeneration, partially via antiinflammatory mechanisms and the PI3K/Akt/caspase 3 pathway. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD and might elucidate the molecular mechanisms of simvastatin effects in PD.