Recent studies have shown that early diagnosis and intervention promote the patient's good prognosis. For patients who underwent cardiac surgery and require extracorporeal circulation support, the incidence of postoperative cognitive dysfunction (POCD) is higher than in other types of surgery due to greater changes in brain perfusion compared with normal physiological conditions. Recent studies have confirmed that the use of ulinastatin or dexmedetomidine in the perioperative period effectively reduces the incidence of POCD. In this study, ulinastatin was combined with dexmedetomidine to assess whether the combination of the two drugs could reduce the incidence of POCD. One hundred and eighty patients with heart valve replacement surgery undergoing cardiopulmonary bypass from August 2017 to December 2018 were enrolled, with age 60-80 years, American Society of Anesthesiologists (ASA) grades I-III, education level above elementary school, and either gender. According to the random number table method, patients were grouped into ulinastatin + dexmedetomidine (U+D) group, ulinastatin (U) group, dexmedetomidine (D) group, and normal saline (N) control group. Group U was pumped 20,000 UI/kg immediately after induction and the first day after surgery, group D continued to pump 0.4 μg/kg/h from induction to 2 h before extubation, group U+D dexmedetomidine 0.4 μg/kg/h + ulinastatin 20,000 UI/kg, and group N equal volume of physiological saline. The patients were enrolled with Mini-Mental State Examination (MMSE) before surgery. The cognitive function was assessed by Montreal Cognitive Assessment (MoCA) on the first day before surgery and on the seventh day after surgery. Inflammatory factors, such as S100β protein, interleukin (IL)-6, matrix metalloproteinase (MMP)-9, and tumor necrosis factor (TNF)-α, were detected in peripheral blood before anesthesia (T0), immediately after surgery (T1), and immediately after extubation (T2). One hundred and fifty-four patients enrolled in this study. Compared with group N, the incidence of POCD in group U+D was the lowest ( < 0.05), followed by group U and group D. Group U+D had the lowest concentration of inflammatory factors at the T1 and T2 time points, followed by group U and group D. Both ulinastatin and dexmedetomidine can reduce the perioperative inflammatory response and the incidence of POCD in patients with heart valve surgery, and their combination can better reduce the incidence of POCD.