Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with post-traumatic seizures (PTS) representing a frequent and potentially devastating complication. While phenytoin has historically been the standard agent for early PTS prophylaxis, levetiracetam has emerged as an increasingly popular alternative despite limited high-quality comparative data. Objective: This systematic review aimed to summarize available evidence on the comparative effectiveness of levetiracetam and phenytoin for seizure prophylaxis following traumatic brain injury. Methods: A comprehensive literature search was performed across PubMed/MEDLINE, Embase, Scopus, and Web of Science for studies published within the last five years. Studies were included if they compared levetiracetam and phenytoin (or fosphenytoin) for PTS prophylaxis in TBI patients of any age. The primary outcome was incidence of early post-traumatic seizures (EPTS; ≤7 days post-injury). Risk of bias was assessed using the Newcastle-Ottawa Scale for cohort studies and the Joanna Briggs Institute checklist for cross-sectional studies. Due to substantial heterogeneity, a narrative synthesis was conducted. Results: Six studies met inclusion criteria, comprising 65,446 TBI patients and 220 clinicians. Studies demonstrated that levetiracetam and phenytoin have comparable efficacy in preventing EPTS. After adjustment for confounders, no significant difference in seizure occurrence was observed between agents (p>0.05 for all comparative analyses). Prophylactic antiseizure medication overall significantly reduced EPTS incidence compared with no prophylaxis (9.6% vs. 32.1%; p<0.001). Neither drug effectively prevented late post-traumatic seizures (>7 days). Levetiracetam offered practical advantages including no requirement for routine serum monitoring, and demonstrated a favourable adverse effect profile, though one meta-analysis reported a modest mortality signal requiring further investigation. Risk of bias was low in two studies, moderate in four studies. Conclusion: Levetiracetam and phenytoin demonstrate comparable efficacy for early post-traumatic seizure prophylaxis after TBI. Neither agent prevents late seizures, supporting current guideline recommendations limiting prophylaxis to the first 7 days post-injury. Clinicians may reasonably choose either agent based on patient-specific factors, institutional protocols, and drug availability.