Introduction: Delirium, being a common disorder among critically ill patients, has a reported incidence ranging 45–83% in the intensive care unit (ICU) population. The prophylactic use of melatonin and melatonergics has been shown to have a positive effect in reducing the incidence of delirium in many clinical trials. Our study was thus proposed to find out the role of melatonin on the incidence and severity of ICU delirium, ICU and hospital length of stay (LOS), requirement, duration of mechanical ventilation, and ICU mortality. Methodology: A systematic search of various databases was performed to find out the trials which compare melatonin with a placebo or standard therapy for delirium prevention with the results conveyed as mean differences (MDs) or risk ratios. The statistical software, Review Manager (RevMan, version 5.4), was used for data synthesis. Results: Twelve studies were included in the meta-analysis. Prophylactic administration of melatonin or ramelteon was not associated with a statistically significant reduction in the incidence of delirium (odds ratio [OR] 0.63; confidence interval [CI]: 0.60, 1.32; p = 0.22), the severity of delirium (MD: 0.22; 95% CI: From −1.36 to 1.81; p = 0.78), ICU LOS (MD: 0.05; 95% CI: From −0.65 to 0.75; p = 0.89), hospital LOS (MD: −1.46; 95% CI: From −4.50 to −1.59; p = 0.35), need for mechanical ventilation (OR: 0.74, 95% CI: 0.38−1.44; p = 0.37), and ICU mortality (MD: 0.78; 95% CI: 0.56; 1.11; p = 0.62). However, a significant reduction in the duration of mechanical ventilation (MD: −0.85; 95% CI: From −1.64 to −0.06; p = 0.03) was found. Conclusion: Our meta-analysis suggests that melatonin when given prophylactically has no significant role in reducing the incidence and severity of delirium, ICU and hospital LOS, need for mechanical ventilation, duration of mechanical ventilation, and ICU mortality. Further studies are warranted.