Recent studies demonstrated that overexpression of the molecular chaperone 14-3-3ζ protects the brain against endoplasmic reticulum (ER) stress and prolonged seizures. The 14-3-3 targets responsible for improved neuronal survival after seizures remain unknown. Here we explored the mechanism, finding that protein levels of the ER-stress-associated transcription factor C/EBP homologous protein (CHOP) were significantly higher in 14-3-3ζ-overexpressing mice. Since previous studies by us demonstrated that loss of CHOP increased vulnerability to seizure damage, we explored whether elevated CHOP levels result from 14-3-3ζ overexpression and contribute to the protection. Pull-down experiments suggested that 14-3-3ζ could bind CHOP as well as sequester a CHOP-targeting microRNA. However, 14-3-3ζ overexpression remained protective against seizure-induced hippocampal injury in mice lacking CHOP. These studies reveal a novel function for 14-3-3ζ in regulating CHOP levels but show that this is not required for protection against seizure-induced neuronal death.