Background: Isolated traumatic brain injury (TBI) accounts for 30% of injury-related deaths globally, with significant cost to individual health, lifestyle and the economy. Despite advances in prehospital trauma care, frontline paramedics have limited options to manage cerebral oedema and herniation. Prehospital osmotherapy could limit cerebral oedema and subsequent secondary brain injury, but uncertainties remain of its benefit to patient outcomes. Aim: This study aimed to explore whether prehospital osmotherapy such as hypertonic saline (HTS) could improve mortality and neurological outcomes in adults with severe isolated TBI compared with other products. Methods: Multiple electronic databases (PubMed, MAG Online Library, EMBase and Cochrane Library) were searched to investigate the impact of prehospital osmotherapy on mortality and neurological outcome. Findings: 9005 articles were identified, with six articles fully meeting the research aim. The majority of literature was high quality with an overriding consensus that administration of prehospital HTS or other hyperosmolar products had limited benefit to patient mortality and neurological outcome in isolated TBI. Conclusion: High-quality literature demonstrated that there is no current strong argument to adopt prehospital osmotherapy for isolated TBI. Paramedics should prioritise managing hypoxia and hypotension, which have proven impacts on long-term mortality and neurological outcomes. Future research should focus on the benefits of the expansion of rapid sequence intubation to advanced paramedics and appropriate analgesia (ketamine) for paramedics to enhance isolated TBI management in UK paramedic practice. However, paramedics should not disregard the importance of fundamental basic resuscitation skills in isolated TBI.