Abstract Objectives Hypertonic saline solutions are increasingly used to treat increased intracranial pressure following severe traumatic brain injury. However, whether hypertonic saline provides superior management of intracranial pressure and improves outcome is unclear. We thus conducted a systematic review to evaluate the effect of hypertonic saline in patients with severe traumatic brain injury. Methods Two researchers independently selected randomized controlled trials studying hypertonic saline in severe traumatic brain injury and collected data using a standardized abstraction form. No language restriction was applied. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and BIOSIS databases. We searched grey literature via OpenGrey and National Technical Information Service databases. We searched the references of included studies and relevant reviews for additional studies. Results Eleven studies (1,820 patients) were included. Hypertonic saline did not decrease mortality (risk ratio 0.96, 95% confidence interval [CI] 0.83 to 1.11, I 2 =0%) or improve intracranial pressure control (weighted mean difference −1.25 mm Hg, 95% CI −4.18 to 1.68, I 2 =78%) as compared to any other solutions. Only one study reported monitoring for adverse events with hypertonic saline, finding no significant differences between comparison groups. Conclusions We observed no mortality benefit or effect on the control of intracranial pressure with the use of hypertonic saline when compared to other solutions. Based on the current level of evidence pertaining to mortality or control of intracranial pressure, hypertonic saline could thus not be recommended as a first-line agent for managing patients with severe traumatic brain injury.