Background: Prehospital management of severe traumatic brain injury (TBI) focuses on preventing secondary brain injury. Therefore, hypotension should be prevented, or if present, should be promptly treated in order to maintain optimal cerebral perfusion pressure. Fluid resuscitation is a traditional mainstay in the prehospital treatment of hypotension, however, the choice of fluid type that is to be administered in the prehospital setting is the subject of an on-going debate. This systematic review and meta-analysis was therefore performed to assess the effect of different fluid types on outcome in patients with severe TBI. Methods: PubMed, Embase and Web of Science were searched for articles up to March 2020. Studies comparing two or more prehospital administered fluid types with suspected or confirmed severe TBI were deemed eligible for inclusion. Studied outcomes were mortality and (extended) Glasgow Outcome Scale (GOS). The meta-analysis tested for differences in survival between hypertonic saline (HTS) and normotonic crystalloids (i.e. normal saline or Lactated Ringer's) and between hypertonic saline with dextran (HSD) and normotonic crystalloids. The systematic review is registered in the PROSPERO register with number CRD42020140423. Results: This literature search yielded a total of 519 articles, of which 12 were included in the systematic review and 6 were included in the meta-analysis. Eleven studies found no statistically significant difference in survival between patients treated with different fluid types (e.g. normal saline and hypertonic saline). All studies assessing neurological outcome, measured through (extended) GOS, found no statistically significant difference between different fluid types. Meta-analysis showed no better survival for patients treated with HSD, when compared to normotonic crystalloids (overall RR 0.99, 95% CI 0.93–1.06). Moreover, HTS compared to normotonic crystalloids does not result in a better survival (overall RR 1.04, 95% CI 0.97–1.12). Conclusions: This systematic review and meta-analysis did not demonstrate a survival or neurological benefit for one specific fluid type administered in the prehospital setting.