Introduction Ramelteon, a melatonin agonist, is a safe and effective hypnotic medication. Small prospective studies, case reports and some randomized, placebo-controlled trials and previous meta-analyses have shown that it can reduce the risk of developing delirium. Assessing the efficacy of ramelteon for delirium prevention have shown mixed results. The goal of this systemic review and meta-analysis was to assess the current evidence supporting the use of ramelteon in delirium prevention including data from more recent larger trials. Methods Medline, Embase, PsycINFO, EBM Reviews, Scopus, and Web of Science databases were queried using the search terms delirium (with sub-terms including prevention and control), ramelteon, ramelteon or rozerem or melatonin receptor agonists, for English-language publications until March 16, 2021 of randomized, placebo-controlled trials in humans. Randomized, placebo-controlled trials of hospitalized subjects receiving ramelteon or placebo for delirium prevention were examined. The primary outcome of interest was delirium incidence. Odds ratios of the risk of developing incident delirium and 95% CIs were calculated using a random effects model. Results A total of 177 articles were identified by the literature search. Five studies (n = 443, 53.7% male) met criteria for inclusion in the final meta-analyses. Use of ramelteon was not associated with a reduction in the risk of incident delirium (n = 443; OR = 0.49; 95% CI, 0.13 to 1.85, I2 = 53%). Conclusions Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients. This research was funded by N/A Ramelteon, a melatonin agonist, is a safe and effective hypnotic medication. Small prospective studies, case reports and some randomized, placebo-controlled trials and previous meta-analyses have shown that it can reduce the risk of developing delirium. Assessing the efficacy of ramelteon for delirium prevention have shown mixed results. The goal of this systemic review and meta-analysis was to assess the current evidence supporting the use of ramelteon in delirium prevention including data from more recent larger trials. Medline, Embase, PsycINFO, EBM Reviews, Scopus, and Web of Science databases were queried using the search terms delirium (with sub-terms including prevention and control), ramelteon, ramelteon or rozerem or melatonin receptor agonists, for English-language publications until March 16, 2021 of randomized, placebo-controlled trials in humans. Randomized, placebo-controlled trials of hospitalized subjects receiving ramelteon or placebo for delirium prevention were examined. The primary outcome of interest was delirium incidence. Odds ratios of the risk of developing incident delirium and 95% CIs were calculated using a random effects model. A total of 177 articles were identified by the literature search. Five studies (n = 443, 53.7% male) met criteria for inclusion in the final meta-analyses. Use of ramelteon was not associated with a reduction in the risk of incident delirium (n = 443; OR = 0.49; 95% CI, 0.13 to 1.85, I2 = 53%). Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients.