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Background: Over recent years, long-term cognitive deficits, morbidity, and mortality stemming from critical illness were uncovered and in great part attributed to development of delirium during hospital admission. Current recommendations regarding appropriate pharmacologic agents, specifically haloperidol, continue to show the reduction of delirium, but with significant complications. Ongoing research is being conducted to identify more appropriate medications to use as first-line in both prevention and treatment. Objective: To assess the efficacy of ondansetron in the prevention and treatment of delirium in critically ill patients. Study Design: Through systematic literature review of public databases, potential new pharmacologic treatment options were identified. Randomized control trials within the past 10 years utilizing ondansetron as prophylactic or acute treatment were selected for this analysis. Selected studies were compared to determine applicability to treatment algorithms for ICU delirium. Results: In the three studies, ondansetron significantly reduced severity and incidence of delirium. It performed comparatively to haloperidol and is considered a safer drug with a lower side effect profile. Ondansetron was also shown to significantly reduce the incidence of delirium when given prophylactically;however, when compared to dexmedetomidine it was less effective. Incidentally, ondansetron was found to decrease pain after discharge and was associated with improved long-term neuropsychiatric testing. Conclusions: Ondansetron should be considered a potential first-line agent for acute treatment of delirium. Dexmedetomidine would potentially be a more appropriate first line prophylactic DELIRIUM INTERVENTION v agent. Further randomized control trials should be conducted to confirm each of these claims, and should include larger sample sizes, assessment of pain, and long-term follow-up.