This study investigates the protective effects of Lycium barbarum polysaccharides (LBPs) on X-ray radiation-induced damage in rat spinal cord neurons (SCNs) and examines whether this protection is mediated through the activation of autophagy. In vitro and in vivo experiments revealed that high-dose radiation significantly reduced SCN viability and colony-forming ability. However, treatment with 40 mg/L LBP markedly increased cell survival and autophagy levels. Immunohistochemistry and Western blot (WB) analyses demonstrated a significant upregulation of autophagy-related proteins, protein 1 light chain 3-II/I and Beclin-1, in the LBP intervention group. In vivo studies further showed that LBP reduced oxidative stress markers, such as malondialdehyde, and enhanced superoxide dismutase activity in spinal cord tissue. These findings indicate that LBP mitigates neuronal damage caused by ionizing radiation via autophagy activation and antioxidative mechanisms, highlighting its potential as a radioprotective agent.