Introduction Intensive care for patients with severe acute brain injury aims both to treat the immediate consequences of the injury and to prevent and treat secondary brain injury to ensure a good functional outcome. Sedation may be used to facilitate mechanical ventilation, for treating agitation, and for controlling intracranial pressure. Ketamine is an N-methyl-D-aspartate receptor antagonist with sedative, analgesic, and potentially neuroprotective properties. We describe a protocol for a systematic review of randomised clinical trials assessing the beneficial and harmful effects of ketamine for patients with severe acute brain injury. Methods and analysis We will systematically search international databases for randomised clinical trials, including CENTRAL, MEDLINE, Embase, and trial registries. Two authors will independently review and select trials for inclusion, and extract data. We will compare ketamine by any regimen versus placebo, no intervention, or other sedatives or analgesics for patients with severe acute brain injury. The primary outcomes will be functional outcome at maximal follow up, quality of life, and serious adverse events. We will also assess secondary and exploratory outcomes. The extracted data will be analysed using Review Manager and Trials Sequential Analysis. Evidence certainty will be graded using GRADE. Ethics and dissemination The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice.