Emerging evidence indicates that the intestinal microbiota could interact with the central nervous system and modulate multiple pathophysiological changes, including the integrity of intestinal barrier and blood-brain barrier, as well as neuroinflammatory response. In the present study, we investigated the potential role of intestinal microbiota in the pathophysiological process of postoperative cognitive dysfunction. Six-month-old APP/PS1 mice were subjected to partial hepatectomy to establish surgery model and exhibited cognitive dysfunction. The expressions of inflammatory mediators increased and tight junction proteins (ZO-1 and Occludin) levels decreased in the intestine and hippocampus. The 16S ribosomal RNA gene sequencing showed altered β diversity and intestinal microbiota richness after surgery, including genus , , and , as well as family and . Furthermore, prebiotics (Xylooligosaccharides, XOS) intervention effectively attenuated surgery-induced cognitive dysfunction and intestinal microbiota alteration, reduced inflammatory responses, and improved the integrity of tight junction barrier in the intestine and hippocampus. In summary, the present study indicates that intestinal microbiota alteration, the related intestinal barrier and blood-brain barrier damage, and inflammatory responses participate the pathophysiological process of postoperative cognitive dysfunction. Prebiotics intervention could be a potential preventative approach.