Ethanol is a known neurotoxic agent that induces endoplasmic reticulum (ER) stress and apoptosis in nerve cells. The transcription factor CREB is crucial for cell survival under stress; however, its involvement in ethanol-induced endoplasmic reticulum (ER) stress remains poorly understood. We examined the effects of ethanol on wild-type PC12 cells and CREB-overexpressing PC12-CREB cells. Cell viability was evaluated by ATP assays, apoptosis was detected by Hoechst staining, and key proteins involved in ER stress and apoptotic signaling were analyzed by Western blot analysis. Ethanol treatment decreased cell viability and increased apoptosis in wild-type PC12 cells in a time-dependent manner. In contrast, PC12-CREB cells-maintained viability and showed significantly lower apoptotic cell numbers. Ethanol activated markers of ER stress (BiP, CHOP, ATF6) and pro-apoptotic pathways (phosphorylation of JNK and p38 MAPK) in wild-type cells. In CREB-overexpressing cells, CHOP induction and JNK activation were decreased, while the expression of the anti-apoptotic protein Mcl-1 was increased. CREB overexpression protects against ethanol-induced ER stress and apoptosis. This protective effect is mediated through modulation of unfolded protein response (UPR) signaling and regulation of pro-and anti-apoptotic gene expression. These findings underscore a potential role for CREB in attenuating ethanol-induced neurotoxicity.