Objective: To investigate the effects of methylprednisolone on postoperative delirium and cognitive dysfunction (POCD) in patients undergoing cardiac surgery. Methods: A total of 91 patients aged 18–65 years with ASA grade II-III were enrolled in our hospital from January 2017 to January 2018 undergoing cardiac surgery. Patients were randomly divided into two groups according to random sequence number generated by SPSS 19.0: methylprednisolone group (group M, n=46) and placebo group (group P, n=45). The patients in M group were injected methylprednisolone 250mg intravenously before induction of anesthesia and cardiopulmonary bypass. The patients in P group were injected the same amount of 0.9% sodium chloride injection. mini-mental state examination (MMSE) were evaluated before anesthesia (T0), 1 day (T1), 3 day (T3), 7 day (T7) and 30 day (T30) after operation. The levels of S100β, neuron-specific enolase (NSE), IL-1β, IL-6, IL-8 were tested at T0, T1 and T3. Results: The levels of IL-6, IL-1β, IL-8, S100β and NSE in M group were lower than those in P group at T1 and T3 (P<0.05). The number of CD3+, CD4+, CD8+, CD4+/CD8+, natural killer cell in EA group were higher than those in GA group at T2 and T3 (P<0.05). The levels of cortisol, C-reactive protein in EA group were lower than those in GA group at T2 and T3 (P<0.05). There was no significant difference between the two groups in MMSE score at T1, T3, T7 and T30 (P>0.05). Postoperative delirium was not observed in either group. There was no significant difference in the incidences of POCD between the two groups (P>0.05). Conclusion: Intraoperative methylprednisolone can effectively inhibit postoperative inflammatory response in patients undergoing on-pump cardiac surgery, but it can't decrease the incidences of postoperative delirium and POCD.