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Background Delirium after cardiac surgery is associated with adverse outcomes, including prolonged hospital stay, prolonged intensive care unit stay, and increased mortality. Effective preventive interventions and treatments still are largely unknown. Aim This systematic review aimed to gather and summarize the existing evidence from randomized trials concerning interventions studied in the prevention or treatment of delirium in adult patients undergoing cardiac surgery. Methods A systematic review of the literature using a key word strategy and Boolean operators was performed. PubMed and the Cochrane and Scopus databases were searched for pertinent studies until July 2018 (no inception limit). Results Of 2,556 articles identified, 56 studies met the inclusion criteria and were included in the review—39 addressed pharmacologic strategies and 17 nonpharmacologic interventions. Interestingly, 51 (91%) trials focused on delirium prevention and only 5 (9%) on delirium treatment. Most of the analyzed studies were recent double-blind, single-center trials conducted in Europe or North America, with a low risk of bias. Overall, 38 different interventions were identified: 15 (26%) interventions were performed before surgery, 20 (36%) in the operating room, and 21 (38%) after surgery. The most frequently analyzed strategies were the administration of dexmedetomidine, ketamine, antipsychotics, glucocorticoids, propofol, opioids, volatile anesthetics, local anesthetics, and remote ischemic preconditioning. The analyzed strategies were extremely heterogenous, and dexmedetomidine was the most promising measure able to prevent the development of postoperative delirium. Conclusions In the present systematic review of 56 randomized controlled trials that examined 38 interventions, the authors found that dexmedetomidine was the most frequently studied agent and that it might reduce the occurrence of delirium after cardiac surgery.