Postoperative cognitive dysfunction (POCD), a prevalent post-surgical complication, not only hampers patient recovery and prolongs hospital stays but also potentially increases the risk of postoperative mortality. N-methyl-D-aspartate (NMDA) receptors, pivotal for learning, memory, and synaptic plasticity, play crucial roles in the development and progression of POCD. Perioperative factors, such as surgical stress, inflammation, and pain, can result in excessive activation of NMDA receptors. This review synthesizes findings from both preclinical and clinical studies for the first time, discussing the mechanisms by which overactivation of NMDA receptors, triggered by multifactorial perioperative insults such as injury, pain, and inflammation, contributes to the development and advancement of POCD. The aim of this review is to identify effective therapeutic targets for POCD and provide guidance for precision clinical treatment strategies that improve postoperative cognitive function in patients.