Background <p>Apoptosis, oxidative stress, and inflammatory responses are involved in ischemia-reperfusion injury (IRI), a pathological process leading to neuronal damage. B-cell translocation gene 2 (BTG2) regulates cellular injury and apoptosis. However, its role and molecular mechanisms in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury remain unclear.</p> Objective <p>To explore BTG2’s role in OGD/R-induced injury in PC12 cells and its underlying mechanism.</p> Methods <p>Differentially expressed genes (DEGs) in OGD/R-treated PC12 cells were identified. Key pathways were screened out using GO and KEGG. BTG2 expression was silenced using RNA interference. The phosphorylation levels of proteins associated with the mitogen-activated protein kinase (MAPK) pathway were further examined. Rescue experiments were performed using anisomycin, a MAPK pathway activator, to verify the functional involvement of MAPK pathway in BTG2-mediated effects.</p> Results <p>DEGs (<i>n</i> = 115) were identified through bioinformatics analysis, which were mainly enriched in cellular stress responses, cell cycle regulation, and apoptosis-related processes. OGD/R treatment significantly upregulated BTG2 expression in PC12 cells. BTG2 knockdown markedly alleviated OGD/R-induced PC12 cell injury. Mechanistically, BTG2 knockdown significantly suppressed MAPK pathway activation induced by OGD/R. Reactivation of the MAPK pathway by anisomycin partially reversed the protective effects conferred by BTG2 knockdown.</p> Conclusion <p>BTG2 promotes apoptosis, oxidative stress, and inflammatory responses in OGD/R-induced PC12 cell injury, at least partly associated with the activation of the MAPK pathway.</p>