Disruption of the sleep-wake cycle is a risk factor and a prodromal indicator of delirium. Melatonergic agents may thus play a role in the prevention of delirium. Based upon literature search on eight databases, this systemic review and frequentist model network meta-analysis (NMA) aimed to determine the efficacy and tolerability of melatonergic agents in delirium prevention. Six randomized controlled trials (RCTs) were included with a total of 913 adult participants (mean age = 78.8, mean female proportion = 59.4%) investigating the preventive effects of melatonergic agents in patients with high risks of developing delirium. The outcomes of NMA demonstrated significant preventive effects with 5 mg/day of melatonin [Odds Ratio (OR) = 0.21, 95% Confidence Intervals (CIs): 0.07 to 0.64], melatonin (0.5 mg/d) [OR = 0.16 (95% CIs: 0.03 to 0.75)], and ramelteon (8 mg/d) [OR = 0.28 (95% CIs: 0.12 to 0.65)] against placebo groups. According to the surface under the cumulative ranking curve (SUCRA), 0.5 mg/d of melatonin was associated with the best preventive effect. Our findings provided the rationale for recommending low-dose melatonergic agents for delirium prevention in the practice guidelines.