Seizures in infancy are one of the main manifestations of disorders in the central nervous system that can have important etiologies. The development of anticonvulsant drugs and the importance of drug selection in infants, due to more complex underlying etiologies, compared with older ages, explicate the essentiality of executing clinical investigations to appraise the optimal therapeutic approach. The objective of the current investigation is to juxtapose two therapeutic approaches involving intravenous levetiracetam and intravenous phenobarbital in the management of neonatal seizures. This is a randomized controlled clinical trial study on 100 infants who were referred to the Hazrat Masoumeh (S) Hospital in Qom owing to convulsions. Infants with seizure who fulfilled the inclusion criteria were arbitrarily allocated to one of the two intervention cohorts: intravenous levetiracetam or intravenous phenobarbital, and therapeutic responses were compared. There was a substantial relationship between seizure time, seizure etiology, anticonvulsant therapy type, and treatment responsiveness. As a result, the risks of not responding to therapy and increasing the dose were approximately 6 and 5 times higher, respectively, in the group that experienced seizures in the fourth week than in the other groups. Infants with cerebrovascular anomalies were more prone to not responding to treatment. Furthermore, children administered phenobarbital had a 2.5-fold higher chance of not responding to treatment than those given levetiracetam (p = 0.043).