Objective: Intravenous (IV) olanzapine could be an alternative to first-generation antipsychotics for the management of agitation in intensive care unit (ICU) patients. We compared the effectiveness and safety of IV olanzapine to IV haloperidol for agitation management in adult patients in the ICU at a tertiary academic medical center. Methods: A retrospective cohort study was conducted. The primary outcome was the proportion of patients who achieved a Richmond Agitation Sedation Scale (RASS) score of < +1 within 4 hours of IV olanzapine or IV haloperidol administration. Secondary outcomes included the proportion of patients who required rescue medications for agitation within 4 hours of initial IV olanzapine or IV haloperidol administration, incidence of adverse events and ICU length of stay. Results: In the 192 patient analytic cohort, there was no difference in the proportion of patients who achieved a RASS score of < +1 within 4 hours of receiving IV olanzapine or IV haloperidol (49% vs. 42%, p = 0.31). Patients in the IV haloperidol group were more likely to receive rescue medications (28% vs 55%, p < 0.01). There was no difference in the incidence of respiratory events or hypotension between IV olanzapine and IV haloperidol. Patients in the IV olanzapine group experienced more bradycardia (11% vs. 3%, p = 0.04) and somnolence (9% vs. 1%, p = 0.02) compared to the IV haloperidol group. Patients in the IV olanzapine group had a longer median ICU length of stay (7.5 days vs. 5 days, p = 0.04). Conclusion: In this retrospective cohort study, there was no difference in the effectiveness of IV olanzapine compared to IV haloperidol for the management of agitation. IV olanzapine was associated with an increased incidence of bradycardia and somnolence.