Eleutheroside E (EE), a principal active compound of Acanthopanax senticosus, has been shown to have a certain neuromodulation effect. Our previous study indicates that EE protects nerve damage caused by radiation. However, its specific function and underlying mechanism remain unknown. Therefore, the objective of this study is to apply the C. elegans model to illuminate the property and mechanism of EE protecting against nerve damage caused by radiation. Here, we found that EE significantly improved the long-term memory of radiation-damaged C. elegans. Through transcriptome sequencing, the results showed that EE protected radiation-damaged C. elegans mainly through G-protein-coupled receptor and neuropeptide signaling pathways. Further research indicated that EE affected the activity of CREB by cAMP-PKA, Gqα-PLC, and neuropeptide signaling pathways to ultimately improve the long-term memory of radiation-damaged C. elegans. In addition, the activity of Gqα and neuropeptides in AWC neurons and the activity of CREB in AIM neurons might be crucial for EE to function.