Delirium is a serious but potentially avoidable complication in critically ill patients. Various pathophysiological processes have been associated with delirium development; however, neuroinflammation hypothesis and pleiotropic effects are the reasons why HMG-CoA reductase inhibitors have been evaluated for delirium prevention. Statin therapy is associated with favorable outcomes in critically ill patients, but significant variability of results exists in patients who received these agents postoperatively. Study design methodological weaknesses, inconsistent delirium assessment, and lack of information on sedation regimens may have confounded these outcomes. Furthermore, no evidence exists on the type of statin, lipophilic or non-lipophilic, that is associated with the most benefit or when therapy with a statin should be initiated. Thus, the efficacy of HMGM-CoA reductase inhibitors on delirium prevention has not been fully established and non-pharmacological methods should remain mainstay of therapy.