Background: Small studies have described the off-label use of intravenous (IV) olanzapine for the management of acute agitation. Objective: The purpose of this study was to evaluate the efficacy and safety of IV olanzapine to manage acutely agitated patients with neurological injuries. Methods: This was a retrospective analysis of IV olanzapine use in patients admitted to the neurotrauma and neurovascular intensive care units at a single academic center. The primary endpoint was the requirement of additional IV olanzapine, IV benzodiazepine, or IV haloperidol within 60 minutes from the time of first IV olanzapine dose. Secondary safety endpoints included QTc prolongation and respiratory depression. Results: Forty-six patients received IV olanzapine during the study period. One patient required an additional dose of IV olanzapine and two patients received benzodiazepine or antipsychotic agents within 60 minutes of IV olanzapine administration. One patient had a post-administration QTc level >500 ms. Two patients had an increased oxygen requirement, but none required intubation. Conclusion: IV olanzapine appears to be efficacious in reducing the need for sedatives and antipsychotics with low risk for QTc prolongation and respiratory depression in acutely agitated patients with neurological injuries.