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Delirium is a familiar neuropsychological syndrome confronted after cardiac surgery associated with a significant morbidity and mortality. Although several therapeutic options including dexamethasone, rivastigmine, risperidone, ketamine, dexmedetomidine, propofol, and clonidine have been used for delirium prevention, there is still lack of certainty regarding the most effective drug. In the current era of evidence-based medicine, the systematic review (with homogeneity) of randomized controlled trials is regarded as the most precise tool for determining the benefit of a therapeutic intervention. This review article aims to assess the current best available evidence to determine the most effective pharmacologic agent for prevention of delirium post cardiac surgery.