Background: Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide, with intracranial haemorrhage and haematoma expansion representing critical determinants of poor outcomes. Tranexamic acid (TXA), an antifibrinolytic agent, has demonstrated mortality benefits in extracranial trauma, but its efficacy in isolated TBI remains debated, particularly regarding optimal patient selection, timing, and dosing. Objective: To systematically synthesise the available evidence on the efficacy of TXA in reducing mortality and haematoma expansion in patients with isolated traumatic brain injury treated in emergency department or prehospital settings. Methods: A comprehensive literature search of PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Scopus was conducted for the five-year period ending in 2026. Randomised controlled trials, cohort studies, nested substudies, and post hoc analyses evaluating intravenous TXA versus placebo, no TXA, or standard care in adult patients with isolated TBI were included. Primary outcomes were all-cause or head injury-related mortality and radiographic haematoma expansion. Risk of bias was assessed using Cochrane RoB 2 (RCTs) and ROBINS-I (non-randomised studies). Due to substantial heterogeneity, a narrative synthesis was performed. Results: Thirteen studies (n = 24,227 patients) met inclusion criteria, including four RCTs, one prospective cohort, three retrospective analyses, and five secondary/post hoc analyses. In mild-to-moderate TBI (GCS 9–15), TXA significantly reduced mortality (CRASH-3 subgroup: RR 0.78, 95% CI 0.64–0.95; Bian meta-analysis: RR 0.71, 95% CI 0.60–0.85). In severe TBI (GCS 3–8), no mortality benefit was observed in RCTs (RR 0.98, 95% CI 0.91–1.05), while observational studies suggested potential harm due to confounding by indication (Bossers: OR 4.49, 95% CI 1.57–12.87). Haematoma expansion was reduced with TXA in two small RCTs (mean expansion 1.5±1.1 mL vs 4.6±1.9 mL), though the CRASH-3 imaging substudy found no prevention of established haematoma expansion but did show reduced new haemorrhage in patients with reactive pupils (aRR 0.80, 95% CI 0.66–0.98). Early administration (within 2 hours) was consistently associated with improved outcomes. Thromboembolic events were not significantly increased with TXA. A novel imaging biomarker (≥3% voxels in 10–20 Hounsfield unit range) showed promise for predicting TXA responsiveness but requires prospective validation. Conclusions: TXA reduces mortality in isolated mild-to-moderate TBI when administered early (within 2 hours), with the strongest evidence supporting its effect in patients with reactive pupils and smaller baseline bleeding volumes. TXA does not improve survival in severe TBI, and observed harm signals are likely confounded. Emergency physicians should consider early TXA administration in mild-to-moderate TBI with intracranial haemorrhage, while severe TBI patients should follow standard protocols pending further research.