BACKGROUND Postoperative cognitive dysfunction (POCD) may last for days, months or even years, leading to prolonged hospitalization and increased costs, increased mortality, and poor quality of life. Although POCD is an important clinical problem, its prevention, treatment strategies and effects are still limited. Therefore, this study aims to investigate the preventive effect of perioperative probiotic intervention on POCD in elderly patients, and further explore the mechanism of probiotics in improving postoperative cognitive function. METHODS After obtaining ethical approval and written informed consent, 190 patients aged 65 years or older scheduled for elective lower-extremity orthopedic surgery were enrolled in this randomized, single-center, double-blind trial. Enrolled patients were randomized to probiotic or control groups receiving either probiotics or placebo (210 mgx4/dose orally, 2 times/day) from 1 day before surgery to 5 days after surgery. The primary outcome was the cognitive function assessed by Mini-mental State Examination (MMSE) on admission, the first day, the third day and the seventh day after surgery. The secondary outcomes included perioperative changes in plasma IL-1β, IL-6 and BDNF, postoperative pain intensity, perioperative activities of daily living (ADL), faecal microbiota composition and changes of intestinal metabolites   RESULTS: The incidence of POCD in the probiotic group was significantly lower than in the control group (6 of 90 patients [6.7%] vs. 16 of 93 patients [17.2%], P = 0.028). In addition, the plasma levels of proinflammatory cytokines IL-1β and IL-6 were significantly lower and BDNF levels were significantly higher in the probiotic group than in the control group 1-2 days after surgery (U = 173.0, P < 0.01; U = 139.0, P < 0.01; U = 207.0, P < 0.01). CONCLUSIONS Perioperative probiotic intervention can reduce the incidence of POCD in elderly patients, which may improve cognitive function by inhibiting inflammatory response after anesthesia and surgery, and altering the composition of the postoperative gut microbiota and intestinal metabolites.