Perioperative neurocognitive disorder (PND) is a long-term perioperative complication that affects elderly surgical patients. As the aging population continues to grow, the prevention and treatment of PND have become important issues to address. Research has shown that ulinastatin significantly reduces the incidence of PND in elderly patients undergoing various types of surgery, including spinal and abdominal surgeries. However, the underlying mechanisms of this effect remain unclear. Transient receptor potential melastatin 4 (TRPM4) is a Ca2 + -activated, monovalent cation channel associated with many neurological diseases. In the present study, we aimed to investigate the relationship between ulinastatin and TRPM4 in PND and to determine its underlying mechanism. Forty eighteen-month-old male Sprague‒Dawley rats were randomly divided into four groups: the sham group, surgery group (internal fixation of tibial fracture), ulinastatin group (ulinastatin + surgery), and 9-phenanthrol group (TRPM4 channel inhibitor 9-phenanthrol + surgery). The neurocognitive function of the rats was detected using the Y-maze and new object recognition (NOR) tests. We used WB, qPCR, and IF to detect the expression levels of TRPM4 in different groups of rats. We also detected the degree of apoptosis in rat hippocampal cells. Surgery under inhaled sevoflurane anesthesia induced cognitive impairments and elevated the expression of TRPM4 in the hippocampus. Downregulation of TRPM4 expression by ulinastatin or 9-phenanthrol alleviated cognitive impairments after anesthesia and surgery. Furthermore, ulinastatin treatment decreased the level of apoptosis in the hippocampus. Ulinastatin downregulates TRPM4 expression and apoptosis to mitigate cognitive dysfunction in aged perioperative neurocognitive disorder rats, and ulinastatin is a promising neuroprotectant against PND.