Background: This systematic review was conducted to evaluate any interventions to prevent incident delirium, or shorten the duration of prevalent delirium, in older adults presenting to the emergency department (ED). Methods: Health sciences librarian designed electronic searches were conducted from database inception through September 2021. Two authors reviewed studies, and included studies that evaluated interventions for the prevention and/or treatment of delirium and excluded non-ED studies. The risk of bias (ROB) was evaluated by the Cochrane ROB tool or the Newcastle-Ottawa (NOS) scale. Meta-analysis was conducted to estimate a pooled effect of multifactorial programs on delirium prevention. Results: Our search strategy yielded 11,900 studies of which 10 met study inclusion criteria. Two RCTs evaluated pharmacologic interventions for delirium prevention; three non-RCTs employed a multi-factorial delirium prevention program; three non-RCTs evaluated regional anesthesia for hip fractures; and one study evaluated the use of Foley catheter, medication exposure, and risk of delirium. Only four studies demonstrated a significant impact on delirium incidence or duration of delirium—one RCT of melatonin reduced the incidence of delirium (OR 0.19, 95% CI 0.06 to 0.62), one non-RCT study on a multi-factorial program decreased inpatient delirium prevalence (41% to 19%) and the other reduced incident delirium (RR 0.37, 95% CI 0.22 to 0.61). One case–control study on the use of ED Foley catheters in the ED increased the duration of delirium (proportional OR 3.1, 95% CI 1.3 to 7.4). A pooled odds ratio for three multifactorial programs on delirium prevention was 0.46 (95% CI 0.31–0.68, I2 = 0). Conclusion: Few interventions initiated in the ED were found to consistently reduce the incidence or duration of delirium. Delirium prevention and treatment trials in the ED are still rare and should be prioritized for future research.