Aim and Background: Delirium is highly prevalent in the immediate postoperative period following cardiac surgery and adversely impacts outcomes. Melatonin has been increasingly used in pharmacological prevention of delirium. We aimed to synthesize the available evidence concerning the role of melatonin and melatonin agonists in preventing delirium in patients after cardiac surgery. Materials and methods: PubMed, Google Scholar, and Web of Science databases were searched for relevant randomized and non-randomized trials in adults undergoing cardiac surgery investigating melatonin agonists to prevent delirium. Studies incorporating transplants, preoperative organ support, prophylactic antipsychotics, or children were excluded. Risk-of-bias was assessed using Cochrane ROB 2.0 and ROBINS-I tools. A systematic review and meta-analysis were conducted, calculating pooled odds ratio (OR) for the incidence of postoperative delirium using a random effects model with the Mantel–Haenszel method with restricted maximum-likelihood estimator. Trial sequential analysis was also carried out for the primary outcome. Results: Six randomized trials and one non-randomized trial involving 1,179 patients were included. Incidence of delirium was 16.7 and 29.6% in the intervention and comparator groups respectively, indicating a pooled OR of 0.44 [95% confidence interval (CI) 0.27 – 0.71, p = 0.04] favoring melatonin. Two studies had a high risk of bias, and I² statistics indicated significant heterogeneity. However, publication bias was insignificant, and trial sequential analysis indicated the significance of the attained effect size. Conclusion: Based on available studies, perioperative melatonin use significantly decreases postoperative incidence of delirium after adult cardiac surgery. However, the available quality of evidence is low, and larger trials with standardization of nonpharmacological delirium prevention interventions, in high-risk cohorts, and exploring various dosages and regimens should be carried out.