Melatonin has been demonstrated to exert a preventive effect on delirium. This meta-analysis sought to investigate the preventive effects of melatonin and melatonin receptor agonists (ramelteon) on delirium in hospitalized elderly patients.This systematic review and meta-analysis delineates the risk of delirium events in older hospitalized patients with melatonin/ramelteon compared with placebo, incorporating randomized controlled trials published up to 8 July 2024. The databases searched were PubMed, Embase and the Cochrane Library. The primary outcome measures were the incidence of delirium, while the secondary outcome measures were the length of hospital stay and mortality. The results are presented as odds ratios (OR) or mean differences (MD) with a 95% confidence interval. The review of publications was conducted in accordance with the guidelines set forth in the Cochrane Handbook and the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA). This study has been registered with INPLASY (number INPLASY202470044).A total of 2086 patients were included in 13 randomized controlled trials. The primary outcome of this meta-analysis demonstrated a statistically difference in the incidence of delirium between the melatonin and placebo groups in hospitalized elderly patients (OR = 0.59, 95% CI: 0.40-0.87, P < 0.01, I2 = 60%), particularly in those who had undergone surgery (OR = 0.60, 95%CI: 0.40-0.89, P = 0.01, I2 = 53%). No statistically differences were observed in terms of length of stay (MD=-0.07, 95%CI:-1.09-0.94, P = 0.89, I2 = 72%) and mortality (OR = 0.79, 95%CI:0.58-1.06, P = 0.12, I2 = 0%).Melatonin has been demonstrated to exert a protective effect on delirium in elderly patients who are hospitalized, particularly in the context of perioperative care.© 2024. The Author(s).