Oxidative stress and proteotoxic endoplasmic reticulum (ER) stress are interconnected cellular stress processes implicated in neuronal injury. J147 reportedly exerts neuroprotective effects through ATP synthase α-subunit (ATP5A)-associated mitochondrial mechanisms, but whether it protects cells from death under proteotoxic ER stress through the same mechanism remains unclear. Here, we directly compared curcumin, CNB-001, and J147 under glutamate-induced oxytosis and tunicamycin (TM)-induced ER stress in murine hippocampal HT22 cells. MTT reduction assays showed that all three compounds attenuated glutamate-induced cell death, whereas only J147 protected cells from TM-induced cytotoxicity at a submicromolar range. LIVE/DEAD staining confirmed the protective effects of J147 against both stressors. At the molecular level, J147 suppressed the TM-induced upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) at the mRNA and protein levels without suppressing the adaptive ER chaperone glucose-regulated protein 78. ATP5A knockdown attenuated glutamate-induced oxytosis but did not protect against TM-induced cell death, and J147 retained its protective effect after ATP5A knockdown. These findings support stressor-dependent protective actions of J147 involving an ATP5A-associated mechanism against oxidative stress and an ATP5A-independent mechanism associated with suppression of CHOP induction. J147 may therefore provide a useful pharmacological tool for investigating neuronal responses to interconnected oxidative and proteotoxic stress.