Neuronal cell death induced by chronic stress in the central nervous system is a cause of neurological dysfunction. We investigated the neuroprotective potential of a water extract of S. takesimense (WEST) against corticosterone-induced apoptosis in PC12 cells and the possible underlying mechanisms. Cells were pretreated with 50 µg/mL of WEST to evaluate its neuroprotective effect based on endoplasmic reticulum (ER) stress inhibition and mitochondrial function improvement. Pretreatment with WEST prevented corticosterone-induced injury in PC12 cells, resulting in increased cell survival, decreased lactate dehydrogenase (LDH) release, and potent apoptosis inhibition by a reduction in apoptotic nuclei demonstrated by Hoechst 33342 and propidium iodide (PI) double staining, and TUNEL staining. WEST strongly attenuated calcium (Ca²⁺) elevation, inducing the closure of mitochondrial permeability transition pores (mPTPs), which were opened by corticosterone. It also stabilized mitochondrial membrane potential (MMP) loss and inhibited the corticosterone-induced decrease in adenosine triphosphate (ATP) levels. Furthermore, the increased reactive oxygen species (ROS) production induced by corticosterone was prevented in PC12 cells treated with WEST. WEST also downregulated the expression of glucose-regulated protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153), the pro-apoptotic protein Bcl-2-associated X (Bax), cytochrome c, cysteine-aspartic protease (caspase)-9, and caspase-3, and upregulated the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). Thus, WEST exerts a neuroprotective effect by inhibiting the apoptosis pathway in ER stress and the mitochondrial dysfunction induced by corticosterone. These results demonstrate that WEST reduces neuronal damage from the neurotoxicity caused by chronic stress.