Patients with acute brain injury have unique care challenges with regard to achieving adequate analgesia and sedation, creating wide opportunities for newer agents to improve care and expand clinical options. Of key interest in this population is the optimization of neurophysiologic parameters including intracranial pressure, cerebral blood flow, and cerebral autoregulation, with the aim of preventing secondary brain injury and allowing for brain recovery. Cortical spreading depolarizations/depression, seizures, and cerebral vasospasms are all frequent targets of monitoring and intervention in the neuro-intensive care unit. During open or endovascular neurosurgical procedures, stability of both systemic hemodynamics and cerebral perfusion is critical. The choice of sedation can make effective clinical neuromonitoring either maximally effective or nearly impossible. Ketamine has been increasingly demonstrated as a promising primary or adjunctive agent to facilitate all of these goals often while reducing the need for more established sedation agents with less favorable side effect profiles. This chapter reviews an array of specific use cases and supportive data regarding how, when, and why to consider using ketamine in the neurocritical care population.