Anesthesia and surgery (A + S) are risk factors for patients to develop postoperative delirium (POD). However, the pathogenesis of POD remains largely to be determined. We employed battery of behavioral tests including open-filed test (OFT), elevated plus maze test (EPMT) and buried food test (BFT) to investigate the role of oxidative stress in the development of POD and to explore the therapeutic target for POD in mice after A + S (simple laparotomy under 1.4% isoflurane anesthesia). We initially found that 6 hours after A + S, mice failed to alter the behavioral changes in OFT and the adenosine triphosphate (ATP) level in hippocampus. After hierarchical cluster analysis, however, there was a significant change in the behavior tests between POD unsusceptible (non-POD) and susceptible (POD-like) mice. Interestingly, cyclosporine A, an inhibitor of mitochondrial permeability transition pore (mPTP) opening, exerted pharmacologically beneficial effects on symptoms, decreased reactive oxygen species (ROS) and ATP, and increased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) levels in the hippocampus of POD-like mice. These findings suggest that abnormally activated oxidative stress might be involved in the underlying mechanisms of POD. Novel therapeutic agents targeting inhibition of oxidative stress would provide an available strategy for POD treatment.