Traumatic brain injury (TBI) is a major global health concern, contributing significantly to mortality and long-term disability. Tranexamic acid (TXA), an antifibrinolytic agent, has demonstrated potential in reducing mortality in trauma patients, but its specific efficacy and safety in TBI management remain under investigation. This systematic review and meta-analysis aim to evaluate the efficacy and safety of TXA in patients with TBI by synthesizing data from randomized controlled trials (RCTs). A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, and Cochrane CENTRAL databases about the studies conducted from January 2005 up to December 10, 2022. Eligible studies included RCTs involving TBI patients of any age, where the experimental group received TXA, and the control group received a placebo. The primary outcome was total mortality, focusing on the overall survival impact of the intervention. Secondary outcomes included the need for neurosurgical intervention, pulmonary embolism, myocardial infarction, deep venous thrombosis (DVT), and stroke. Data were pooled using the DerSimonian-Laird random-effects model, with heterogeneity evaluated using the Cochrane Q test and I² statistic. Twelve RCTs encompassing 37,482 participants met the inclusion criteria. TXA administration was associated with a significant reduction in total mortality (relative risk (RR) 0.95, 95% confidence interval (CI) 0.90-0.99, P=0.002) compared to placebo, without increasing the risk of thromboembolic events such as DVT (RR 1.07, 95% CI 0.73-1.57, P=0.58) and pulmonary embolism (RR 0.97, 95% CI 0.78-1.22, P=0.82). The analysis showed no significant differences between the TXA and placebo groups concerning the need for neurosurgical intervention, incidence of myocardial infarction, or occurrence of stroke. Additionally, the studies demonstrated low to moderate heterogeneity across the assessed outcomes, indicating consistent findings regarding the treatment intervention and its associated complications. In conclusion, TXA significantly reduces total mortality in TBI patients without elevating the risk of thromboembolic complications. These findings support the integration of TXA into acute TBI management protocols, especially in settings requiring rapid intervention. Nevertheless, further research is necessary to optimize dosing regimens and administration timing and to assess the long-term functional outcomes associated with TXA use in TBI patients.