Background: Oxygen supplementation is recommended after traumatic brain injury (TBI) but excessive oxygen may be harmful. The aim of this study was to investigate the effect of supplemental oxygen or high/low inspiratory oxygen fraction (FiO₂) for TBI patients on in-hospital mortality. Methods: We searched Medline (Pubmed), EMBASE and the Cochrane Library for interventional and observational studies fulfilling the following criteria: TBI patients >17 years (population); initial use of supplemental oxygen/high (≥0.6) FiO₂ (intervention) vs no supplemental oxygen/low (<0.6) FiO₂ (control) for spontaneously breathing or mechanically ventilated TBI patients, respectively with in-hospital mortality as primary outcome. Secondary outcomes were 30-day and 1-year mortality, length of stay in hospital or intensive care unit, days on mechanical ventilation, complications, and neurological impairment. Results: We screened 4846 citations. Two interventional studies comparing high vs low FiO₂ for mechanically ventilated TBI patients were included. No difference in in-hospital mortality was found. The first study found a statistically significant shorter length of stay in the intensive care unit for the high FiO₂-group (6.5 [4.6–11.4] vs. 11.4 [5.8–17.2] days, p = 0.02). The second study found a lower disability at 6 months in the high FiO₂-group with low disability in 25 (73.5%) vs. 15 (44.1%), moderate disability in 9 (26.5%) vs. 16 (47.1%), and severe disability in 0 (0.0%) vs. 3 (8.8%), p = 0.02. Conclusion: Evidence on the effect of initial use of high/low FiO₂ for TBI patients on in-hospital mortality was extremely limited. Evidence on the use of supplemental oxygen for spontaneously breathing TBI patients is lacking.