INTRODUCTION: Seizures are the most common neurologic emergency in the neonatal period. Phenobarbital and levetiracetam are the most commonly used anti-epileptic agents. However, there is conflicting evidence regarding their efficacy and safety. This review aims to synthesize data from randomized trials evaluating levetiracetam versus phenobarbital as a first-line antiepileptic drug for seizures in the newborn. METHODS: A systematic review and meta-analysis following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines was performed. The review considered randomized clinical trials (RCTs) providing information about the efficacy and safety of levetiracetam vs phenobarbital as first line treatment of neonatal seizures. Medline by PubMed, CENTRAL by Cochrane, Embase, Google Scholar, and grey literature for RCTs were searched. RESULTS: Four randomized controlled trials met the criteria for inclusion. A total of 312 neonates (levetiracetam n=167, phenobarbital n=145) comprised the pooled sample. Seizure freedom did not significantly favour one particular drug. This was also seen throughout subgroup analysis comprising clinical determination of seizure onset and cessation and neonates with hypoxic-ischemic encephalopathy. Significant heterogeniety was seen throughout the analyses. Hypotension was seen more in patients given phenobarbital. No significant association of either drug was seen for respiratory abnormalities and requirement for ventilation. Mortality was not significantly associated with either drug. CONCLUSION This meta-analysis combined and synthesized data from four randomized controlled trials comparing levetiracetam and phenobarbital in efficacy and safety for neonatal seizures. The statistical analysis did not lend evidence to support the use of one drug over the over. More studies that employ stringent techniques to minimize bias are needed for a more robust conclusion.