Objective: To investigate the protective effect of Ganoderma atrum polysaccharide (PSG-1) against lipopolysaccharide (LPS)-induced damage in intestinal epithelial cell (IEC-6) and its underlying mechanisms. Methods: The intervention effects of PSG-1 on IEC-6 cells were investigated using a LPS-induced intestinal epithelial cell IEC-6 injury model， and the effect of PSG-1 intervention on cell viability was assessed using the cell counting kit-8 (CCK-8) assay. Western blot technology was employed to investigate the alterations in the expression of intestinal tight junction proteins and cyclooxygenase-2 (cox-2) in the cells. Transcriptome sequencing analysis was conducted to explore the potential protective mechanisms of PSG-1， followed by experimental validation. Results: Intervention with PSG-1 significantly enhanced cell viability and the expression of intestinal barrier proteins， including ZO-1， Claudin-1， and Occludin. Moreover， PSG-1 exhibited an inhibitory effect on the abnormal upregulation ofcox-2 induced by LPS. Transcriptome sequencing analysis， scratch assay， and western blot experiments validation demonstrated that PSG-1 significantly enhanced cell migration ability while suppressing the expression of pro-apoptotic proteins， including Bax， Caspase-3， and Caspase-9. Conclusion: PSG-1 exhibited significant improvement in LPS-induced damage in IEC-6 cell. Cell migration and apoptosis might be key mechanisms through which PSG-1 exerted its protective effects.