Background <p>Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. Erythropoietin (EPO) has been proposed as a potential neuroprotective agent due to its anti-apoptotic, anti-inflammatory, and neurogenic properties. This meta-analysis evaluates the impact of EPO administration on mortality, neurological recovery, and complications in patients with TBI.</p> Methods <p>A comprehensive literature search identified relevant RCTs and observational studies assessing the efficacy and safety of EPO in TBI. Data extraction included study characteristics, the quality assessment of the research, and primary outcomes: hospital mortality, short-term mortality, mid-term mortality, and favorable neurological outcome, along with the complications for the secondary outcomes.</p> Results <p>11 studies were included in this meta-analysis consisting of 8 RCTs and 3 observational studies. The analysis demonstrates the promising effect of EPO in reducing short-term and mid-term mortality. However, EPO did not significantly improve either acute mortality or favorable recovery. Overall, the findings of the complication analysis suggested no significant difference between the EPO and control groups.</p> Conclusions <p>This comprehensive meta-analysis highlights the potential benefits of EPO in reducing short and mid-term mortality in TBI patients. The promising results of EPO administration warrant further consideration in treatment protocols as it did not show any impact or cause any complications. Our findings contribute valuable insights, guiding evidence-based clinical decision-making and promoting advancements in TBI management.</p> PROSPERO Registration Number <p>CRD42024576372.</p>