Background Neonatal seizures are a common neurological emergency that requires immediate treatment to prevent long-term complications. Phenobarbital has been widely used as the first-line anticonvulsant, but concerns regarding its safety and potential impact on neurodevelopment have led to the exploration of alternative treatments. Levetiracetam has emerged as a promising option with a better safety profile. This study aimed to compare the efficacy and safety of levetiracetam and phenobarbital in the management of neonatal seizures. Methods This randomized controlled trial was conducted at CMC Children's Hospital, Larkana, from January 2023 to January 2024. A total of 101 neonates with clinically or electrographically confirmed seizures were enrolled and randomly assigned to receive either levetiracetam or phenobarbital. The primary outcome was seizure cessation within 24 hours, while secondary outcomes included time to seizure control, need for rescue therapy, adverse effects, and neurodevelopmental outcomes at six months. Data were analyzed using SPSS, with statistical significance set at p < 0.05. Results Keywords Seizure cessation was achieved in 82% of neonates in the levetiracetam group compared to 70.6% ‘in the phenobarbital group, though the difference was not statistically significant (p=0.19)’. However, the time to seizure control was significantly shorter in the levetiracetam group (p=0.02). Neonates treated with phenobarbital experienced ‘a higher incidence of respiratory depression (p=0.04) and required more frequent mechanical ventilation (p=0.04)’. Severe sedation was also significantly more common with phenobarbital (p=0.004). At six months, neurodevelopmental delay ‘was observed in 24% of the levetiracetam group and 41.2% of the phenobarbital group (p=0.05), suggesting better long-term outcomes with levetiracetam’. Conclusion Levetiracetam demonstrated comparable efficacy to phenobarbital in seizure control while offering a faster response and a significantly better safety profile. The findings suggest that levetiracetam may be a preferable first-line treatment for neonatal seizures, particularly in cases where the risk of respiratory depression and excessive sedation needs to be minimized. ‘Further studies with larger sample sizes and longer follow-ups are needed to confirm its long-term’ neurodevelopmental benefits.