Background: Postoperative cognitive dysfunction (POCD) is associated with neuroinflammation by triggering the systemic inflammatory responses. Related studies have demonstrated that ulinastatin, which is a urinary trypsin inhibitor, inhibited the release of inflammatory mediators and improved postoperative cognitive function in elderly patients undergoing major surgery. However, there are controversial results put forwarded by some studies. This systemic review aimed to evaluate the effect of ulinastatin on POCD in elderly patients undergoing surgery. Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, and Ovid to find relevant randomized controlled trials (RCTs) of ulinastatin on POCD in elderly patients undergoing surgery. The primary outcomes included the incidence of POCD and the Mini-Mental State Examination (MMSE) scores. The secondary outcome was the levels of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, S100 beta, C-reactive protein (CRP), interleukin (IL)-6, and IL-10. RevMan 5.3 was used to conduct the meta-analysis. Results: Ten RCTs were included finally. Compared with controls, ulinastatin significantly reduced the incidence of POCD [risk ratio (RR) = 0.29, 95% CI 0.21-0.41, test of RR = 1: Z = 7.05, p < 0.00001]. In addition, patients in the ulinastatin group have lower levels of TNF-alpha, S100 beta, CRP, and IL-6 and higher level of IL-10 in serum following surgery. Conclusion: These findings suggested that ulinastatin can be used as an anti-inflammatory drug for POCD prevention in elderly patients undergoing surgery. Systematic Review Registration Number: CRD42019137449.