Background <p>The optimal red blood cell transfusion (RBCT) strategy for traumatic brain injury (TBI) patients remains a topic of debate. This systematic review and meta-analysis aimed to compare the outcomes of a liberal transfusion strategy versus a restrictive strategy in critically ill patients with TBI.</p> Methods <p>PubMed, Web of Science, Embase, and Cochrane Library were searched from inception to November 17, 2024. We included randomized controlled trials (RCTs) of critically ill adult patients with TBI, reporting data on RBCT strategies. The outcomes included intensive care unit (ICU) mortality, long-term mortality, unfavorable functional outcomes, and the incidence of adverse events, such as transfused acute respiratory distress syndrome (TARDS) and venous thromboembolism. We also performed subgroup analyses comparing the association between disease severity and long-term mortality. This review was submitted to PROSPERO (Registration number: CRD42024558797).</p> Results <p>In the results, our analysis revealed that compared to a restrictive transfusion strategy, a liberal strategy did not significantly reduce the risk of ICU mortality (RR: 0.74; 95% CI 0.28–1.91; <i>P</i> = 0.53) and long-term mortality (RR: 1.02; 95% CI 0.83–1.25; P = 0.87), but it was able to reduce the risk of unfavorable functional outcomes (RR: 0.90; 95% CI 0.82–0.98; <i>P</i> = 0.01), although there may be a false positive error. In addition, the liberal transfusion strategy was associated with a higher incidence of Transfused Acute Respiratory Distress Syndrome (TARDS) (RR: 1.78; 95% CI 1.06–2.98; <i>P</i> = 0.03).</p> Conclusions <p>In critically ill patients with TBI, a liberal RBCT strategy appears to improve functional outcomes but carries the risk of false positive errors. In addition, this strategy does not seem to improve survival and may increase the risk of TARDS. Despite this, there remains insufficient evidence to recommend either strategy in this population.</p>