There is a need for novel neuroprotective therapies. We aimed to review the evidence for exogenous vitamin C as a neuroprotective agent. MEDLINE, Embase, and Cochrane library databases were searched from inception to May 2020. Pre-clinical and clinical reports evaluating vitamin C for acute neurological injury were included. Twenty-two pre-clinical and 11 clinical studies were eligible for inclusion. Pre-clinical studies included models of traumatic and hypoxic brain injury, subarachnoid and intracerebral hemorrhage, and ischemic stroke. The median [IQR] maximum daily dose of vitamin C in animal studies was 120 [50-500] mg/kg. Twenty-one animal studies reported improvements in biomarkers, functional outcome, or both. Clinical studies included single reports in neonatal hypoxic encephalopathy, traumatic brain injury, and subarachnoid hemorrhage and eight studies in ischemic stroke. The median maximum daily dose of vitamin C was 750 [500-1000] mg, or ∼10 mg/kg for an average-size adult male. Apart from one case series of intracisternal vitamin C administration in subarachnoid hemorrhage, clinical studies reported no patient-centered benefit. Although pre-clinical trials suggest that exogenous vitamin C improves biomarkers of neuroprotection, functional outcome, and mortality, these results have not translated to humans. However, clinical trials used approximately one tenth of the vitamin C dose of animal studies.