Objective To investigate the effect of sivelestat sodium on early postoperative recovery of elderly patients undergoing cardiac valve replacement under cardiopulmonary bypass (CPB). Methods Eighty patients aged 65-78 years and scheduled to elective heart valve replacement under CPB in the operating room of our hospital were recruited and divided into control group (group C) and sivelestat sodium group (group S), according to a random number table method, with 40 cases in each group. The patients in group S were infused with civelestat sodium injection at a rate of 0.2 mg·kg-1·h-1 intravenously 10 minutes before anesthesia until the mechanical ventilation was weaned off. Patients in group C were injected with normal saline at the same rate. Peripheral venous blood was drawn 1 day before operation and 1 day and 3 days after operation, and blood routine was determined. Postoperative delirium (POD) was assessed by the intensive care unit (ICU) consciousness disturbance assessment method (CAM-ICU) within 3 days after the operation. Neurocognitive testing was performed preoperatively, at discharge, and 3 months postoperatively, and postoperative cognitive dysfunction (POCD) and dementia (AD) were assessed using the Mini-Mental State Examination Scale (MMSE), with exclusion of preoperative patients with <24 points. Intraoperative and postoperative adverse events including sinus bradycardia or hypotension/hypertension, postoperative infection, etc. were recorded. The length of hospital stay and 90-day mortality were recorded. After 3 months, data related to sleep, quality of life, anxiety and pain were collected using questionnaires. Results A total of 13 patients (32.5%) in group C developed POD within 3 days after surgery and there was a significant difference between the groups (P<0.05). A total of 5 patients (12.5%) in group S developed POD within 3 days after surgery. The white blood cell count, neutrophil count and percentage of neutrophils in the two groups at 1 d and 3 d after operation were all higher than those at 1 d before operation, but the indexes in group S was significantly lower than those in group C (P<0.05). Compared with group C, postoperative mechanical ventilation time and ICU stay time were significantly shortened in group S (P<0.05). At the 90-day follow-up, there was no difference in the MMSE score compared with the baseline (P>0.05). A total of 4 patients (10%) developed neurocognitive dysfunction after surgery. There was no difference in the incidence of POCD between the two groups (P>0.05). The incidence of adverse events such as bradykinesia, hypotension/hypertension, and postoperative infection were similar between the two groups, and there was no significant difference (P>0.05). During the 90-day follow-up period after surgery, no patient died in either group. There was no significant difference in postoperative hospital stay between the two groups (P>0.05). Using the EQ-5D questionnaire to evaluate the quality of life of the two groups of patients, the results showed that there was no statistically significant difference between the two groups (P>0.05). At 3 months after operation, there was no significant difference in sleep quality between the two groups (P>0.05). Conclusion Sivelestat sodium can lower the incidence of POD, shorten postoperative duration of mechanical ventilation and ICU stay, and be beneficial for early postoperative recovery in elderly patients with heart valve replacement under CPB