Stomatin-like protein-2 (SLP-2) has emerged as a cytoprotective protein that confers a protective effect against various stresses. However, whether SLP-2 confers neuroprotection during cerebral ischemia/reperfusion injury remains unclear. In the present study, we investigated the role of SLP-2 in regulating oxygen-glucose deprivation/reoxygenation (OGD/R)-induced apoptosis and oxidative stress, which has been used as an in vitro model of cerebral ischemia/reperfusion injury. We found that OGD/R treatment resulted in a significant reduction in SLP-2 expression in neurons. Functional experiments demonstrated that SLP-2 overexpression significantly increased cell viability and decreased cell apoptosis and reactive oxygen species (ROS) production in OGD/R-exposed neurons, while SLP-2 inhibition showed the opposite effect. Notably, SLP-2 overexpression was shown to up-regulate the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). In addition, SLP-2 overexpression increased the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 and reinforced the activity of Nrf2/antioxidant response element (ARE)-mediated transcription. However, AMPK inhibition or Nrf2/ARE inhibition partially reversed SLP-2-mediated neuroprotection effect in OGD/R-exposed neurons. Taken together, these results demonstrate that SLP-2 confers neuroprotection effect in OGD/R-injured neurons associated with reinforcing AMPK/Nrf2 signalling, suggesting SLP-2 as a potential therapeutic target for cerebral ischemia/reperfusion injury.