GTM-1 is a drug that reverses Alzheimer’s Disease (AD) development specifically induced by thapsgargin (TG) and endoplasmic reticulum (ER) has been reported to be a pilot process that leads to AD formation. It is speculated that GTM-1 could also prohibit TG-induced ER stress. In this study, we utilized immuno-fluorescence to identify morphological changes in nucleus and transmission electron microscopy was used to observe neuronal ultra-structures. Moreover, expressions of GRP78, CHOP, Bcl-2 and cytochrome c were assessed using immuno-blotting, while calcium concentration was detected by fluorescence spectrometer. As suggested by the above cellular experiments, neuronal ultrastructures were damaged by the treatment of TG, while this damaging trend was reversed when neurons were simultaneously treated with both TG and GTM-1. Besides that, certain marker proteins of ER stress (e.g. GRP78, CHOP, and cytochrome c) and calcium concentrations in neurons were significantly increased when TG was applied, while these levels were reduced to normal conditions when GTM-1 was added in the treatment. In conclusion, GTM-1 restrained the ongoing of ER stress that was induced by TG.