Endoplasmic reticulum (ER) stress has been demonstrated to contribute to neurodegeneration in multiple nervous system diseases. Wogonin is a flavonoid isolated from Scutellaria baicalensis root and has multiple pharmacological effects, including anti-inflammatory, antioxidant, and anticancer effects. It has a protective role in nervous system diseases; however, the pharmacological function of wogonin in the spinal cord is still with limited acquaintance. In the present study, rat dorsal root ganglion (DRG) neurons were pretreated with different concentrations of wogonin (0-100 μM) before inducing ER stress using tunicamycin (TUN) (0.75 μg/ml). Wogonin pretreatment at 75 and 100 μM had a cytoprotective effect on cells against TUN-induced toxicity. Wogonin also decreased the number of the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive DRG neurons and increased expression of superoxide dismutase (SOD), which was accompanied by decreased malondialdehyde (MDA) level. The induction of apoptosis was prevented with reduction in expression level of Bax and concomitant increase in B cell lymphoma 2 (Bcl-2) level. Furthermore, wogonin downregulated expression level of ER stress genes coding for glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), active caspase 12, transcription factor 4 (ATF4), and phosphorylation of pancreatic ER stress kinase (PERK) and eukaryotic initiation factor 2 alpha (eIF2α). The current study indicated that wogonin modulated stress-responsive genes, helping DRG neurons prevent TUN-induced ER stress through the PERK-eIF2α-ATF4 signaling pathway.