<b><i>Introduction:</i></b> There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add-on therapy with LEV for achieving &gt;80% seizure reduction after phenobarbital (PB) treatment. <b><i>Methods:</i></b> Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG-confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd-, 3rd- or 4th-line treatment. Antiseizure medication was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography. The total seizure burden in minutes, 2 h before and 4 h after administration of LEV, was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving &gt;80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated. <b><i>Results:</i></b> A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36–44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (<i>n</i> = 11), hemorrhagic or ischemic stroke (<i>n</i> = 16), central nervous system infection (<i>n</i> = 8), genetic (<i>n</i> = 8), metabolic disorders (<i>n</i> = 3), and unknown (<i>n</i> = 1). Following LEV administration, &gt;80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration. <b><i>Discussion:</i></b> Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration.