Background: Preterm neonates with perinatal asphyxia are at high risk of seizures, yet optimal first-line anticonvulsant therapy remains uncertain. Phenobarbitone has traditionally been used but carries significant adverse effects, while levetiracetam offers a potentially safer alternative. This study compared the efficacy and safety of levetiracetam versus phenobarbitone in preterm neonates with post-asphyxial seizures. Methods: This open-label randomized controlled trial enrolled 72 preterm neonates (31 to <37 weeks gestation) with convulsions due to perinatal asphyxia (HIE stage II/III). Neonates were randomized to receive either intravenous levetiracetam (20 mg/kg loading, 10 mg/kg/dose 12 hourly maintenance) or phenobarbitone (20-40 mg/kg loading, 5 mg/kg/day maintenance). Primary outcomes included seizure control, time to seizure cessation and adverse effects. Results: Seizure control with monotherapy was significantly higher in the levetiracetam group (72.22%) compared to phenobarbitone (44.44%) (p=0.004). The need for additional anticonvulsants was substantially lower in the levetiracetam group (27.78% vs. 55.6%, p=0.004). Seizure control within 12 hours was achieved in 83.33% of levetiracetam-treated neonates versus 50.0% in the phenobarbitone group (p=0.039). Adverse effects occurred significantly less frequently with levetiracetam (5.56% vs. 27.78%, p=0.024), with somnolence being the most common adverse effect in both groups. Conclusion: Levetiracetam demonstrated superior efficacy with more rapid seizure control and a significantly better safety profile compared to phenobarbitone in preterm neonates with post-asphyxial seizures. These findings support levetiracetam as a favorable first-line agent in this vulnerable population.