Background: Patients with severe traumatic brain injury (TBI) are at uniquely high risk of venous thromboembolism (VTE), but the benefits of VTE prophylaxis must be weighed against the risk of intracranial hemorrhage expansion. Current guidelines are heterogenous in their recommendations for chemical VTE prophylaxis (cVTEp) in this high-risk cohort. We conducted a systematic review to identify the optimal timing of cVTEp in severe TBI patients. Methods: We executed a systematic search of the literature to identify adult severe TBI patients treated with cVTEp. Results were pooled, analyzed using random-effects models, and presented as Forest plots and odds ratios. Results: We included 21 studies representing 322,735 patients. The odds of VTE were 0.47 (95% CI: 0.37,0.60) when using the authors’ own criteria for early initiation, and the odds of VTE remained significantly decreased in subgroup analysis (<24h, <48 and <72h). Early VTEp both as defined by authors and in subgroup analysis did not significantly impact the odds of hemorrhage progression or mortality; except for initiation <48h which showed a positive impact on mortality (OR: 0.74, 95% CI: 0.63-0.87). Conclusions: This study supports early initiation of cVTEp in reducing the odds of VTE events without significantly increasing the risk of adverse events.