<p>Prostaglandin endoperoxide synthase 2 (PTGS2) is a rate-limiting enzyme of prostaglandin (PGs) production, mediating perioperative inflammatory response. This study aimed to explore the mechanisms underlying the involvement of PTGS2 in postoperative cognitive dysfunction (POCD). Transient bilateral common carotid artery occlusion (tBCCAO) was performed to induce POCD. The Morris water maze test was used to assess the cognitive function. PTGS2 expression in the hippocampus and plasma was measured. Hippocampal RNA sequencing was performed to determine the pathological basis of POCD. In vivo, the mice were treated with or without a selective PTGS2 inhibitor during the perioperative period. The hippocampi were isolated to detect inflammation and oxidative damage. In vitro, PTGS2 was silenced in BV2 microglial cell lines, and oxygen-glucose deprivation/reoxidation (OGD/R) was performed. Conditioned medium from BV2 cells was collected to culture HT22 hippocampal neurons. Proinflammatory factors and oxidative damage were detected in BV2 and HT22 cells, respectively. The results indicated that the expression of PTGS2 in the plasma and hippocampal tissue of POCD mice was increased and that hippocampal inflammation is an important biological process in POCD. Inhibition of PTGS2 alleviated hippocampal inflammation, and the Morris water maze test showed improved learning and memory functions that were previously impaired. In addition, the inhibition of PTGS2 prevents OGD/R-induced microglial activation and alleviates neuronal injury. In conclusion, PTGS2 may be a culprit in POCD.</p>