Neuroprotection is one common strategy to reduce injuries from cerebral ischemia. This study aims to evaluate neuroprotective activity of several representative stilbenes with different substituted groups to preliminarily know about their structure/activity relationship and action mechanisms. Among the stilbenes tested, only pinosylvin showed strong neuroprotective effects, evidenced by the decreased cell death in OGD/R-damaged PC12 cells and improved brain function in MCAO/R rats after pinosylvin treatment. Pinosylvin reduced the rate of depolarized cells (low mitochondrial membrane potential) in OGD/R-damaged PC12 cells, implying its role in improving mitochondrial function. Further studies indicated that pinosylvin induced PINK1/Parkin mediated protective mitophagy and activated Nrf2 pathway, suggested by the elevated protein levels of LC3 II, Beclin1, PINK1 and Parkin, and Nrf2 translocation to nucleus. In conclusion, pinosylvin exhibited neuroprotective effects by inducing PINK1/Parkin mediated mitophagy to remove damaged mitochondria and activating Nrf2 pathway to ameliorate oxidative stress-induced mitochondrial dysfunction.